Combination of cytochome p450 dependent protease inhibitors

ABSTRACT

The present invention relates to a method for improving the pharmacokinetics of hexahydrofuro[2,3-b]furanyl containing HIV protease inhibitors comprising administering to a human in need thereof a combination of a therapeutically effective amount of a hexahydrofuro[2,3-b]furanyl containing HIV protease inhibitor, and a therapeutically effective amount of a cytochrome P 450  inhibitor.

The present invention relates to a method for improving thepharmacokinetics of hexahydrofuro[2,3-b]furanyl containing HIV proteaseinhibitors comprising administering to a human in need thereof acombination of a therapeutically effective amount of ahexahydrofuro[2,3-b]furanyl containing HIV protease inhibitor, and atherapeutically effective amount of a cytochrome P₄₅₀ inhibitor.

The virus causing the acquired immunodeficiency syndrome (AIDS) is knownby different names, including T-lymphocyte virus in (HTLV-III) orlymphadenopathy-associated virus (LAV) or AIDS-related virus (ARV) orhuman immunodeficiency virus (HIV). Up until now, two distinct familieshave been identified, i.e. HIV-1 and HIV-2. Hereinafter, HIV will beused to generically denote these viruses.

One of the critical pathways in a retroviral life cycle is theprocessing of polyprotein precursors by retroviral protease. Forinstance, during the replication cycle of the HIV virus, gag and gag-polgene transcription products are translated as proteins, which aresubsequently processed by a virally encoded protease (or proteinase) toyield viral enzymes and structural proteins of the virus core. Mostcommonly, the gag precursor proteins are processed into the coreproteins and the pol precursor proteins are processed into the viralenzymes, e.g., reverse transcriptase, integrase and retroviral protease.It has been shown that correct processing of the precursor proteins bythe retroviral protease is necessary for the assembly of infectiousvirions. For example, it has been shown that frameshift mutations in theprotease region of the pol gene of HIV prevent processing of the gagprecursor protein. It has also been shown through site-directedmutagenesis of an aspartic acid residue in the HIV protease active sitethat processing of the gag precursor protein is prevented. Therefore,retroviral protease inhibition provides an attractive target forantiviral therapy. In particular for HIV treatment, the HIV protease isan attractive target.

Retroviral protease inhibition typically involves a transition-statemimetic whereby the retroviral protease is exposed to a mimetic compoundwhich binds (typically in a reversible manner) to the enzyme incompetition with the gag and gag-pol proteins to thereby inhibitspecific processing of structural proteins and the release of retroviralprotease itself. In this manner, retroviral replication proteases can beeffectively inhibited.

HIV protease inhibitors (PIs) are commonly adminstered to AIDS patientsin combination with other anti-HIV compounds such as, for instancenucleoside reverse transcriptase inhibitors (NRTIs), non-nucleosidereverse transcriptase inhibitors (NNRTIs) or other protease inhibitors.

Ghosh et al. (Bioorg. Med. Chem. Lett, 1998, 8, 687-690), WO 00/47551and WO 99/33815 disclose certain HIV protease inhibitors comprising ahexahydrofuro[2,3-b]furanyl moiety.

Some antiretrovirals and, in particular, some HIV protease inhibitorsare metabolized by cytochrome P₄₅₀, leading to sub-optimalpharmacokinetic profiles causing an undesired need for more frequent andhigher doses. Thus, there is a high medical need for effective and safeanti-HIV treatment wherein the therapeutic compounds have goodbioavailability, a favorable pharmacokinetic and metabolic profile, andhave reduced side effects.

Several disclosures propose a combination of a protease inhibitor withat least one second compound for the improvement of the pharmacokineticof said first PI. For instance, WO 00/25784 describes a method forimproving the pharmacokinetics of tipranavir comprising a combination oftipranavir and ritonavir. U.S. Pat. No. 6,180,634 discloses asynergistic composition comprising N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(2-benzo[b]furanylmethyl)-2(S)-N′-(t-butyl-carboxamido)-piperazinyl))-pentaneamideand one or more antiretroviral agents such as indinavir. WO 97/01349describes a method for improving the pharmacokinetics of a drug which ismetabolized by cytochrome P₄₅₀ monooxygenase wherein said methodcomprises administering to a patient a composition comprising acombination of said drug with ritonavir. WO 95/10281 describes acombination of a selected protease inhibitor, L-735,524 in combinationwith either cimetidine or ketoconazole. Sadler et al. (AIDS, 2001,15(8), 1009-1018) evaluated the pharmacokinetics and safety ofamprenavir and ritonavir following multiple-dose, co-administration tohealthy volunteers. Tanaka et al. (J. Clin. Pharmacy Therap., 1998, 23,403-416) describe some HIV protease drugs whose metabolism may bedependent on isoforms of cytochrome P₄₅₀. Hsu et al. (ClinPharmacokinet. 1998, 35, 275-291) describes the pharmacokinetics ofRitonavir, including the impact on cytochrome P₄₅₀ isoenzymes.

It is an object of the present invention to provide improvedcombinations of hexahydrofuro[2,3-b]furanyl containing HIV proteaseinhibitors with cytochrome P₄₅₀ inhibitors. It is another object toprovide a combination of hexahydrofuro[2,3-b]furanyl containing HIVprotease inhibitors wherein a further synergistic effect of saidinhibitors is observed upon administration of said composition to apatient in need thereof.

It has been found that the combination of (a) HIV protease inhibitors offormula (1) or a pharmaceutically acceptable salt or ester thereof and(b) an inhibitor of cytochrome P₄₅₀, more specifically of cytochromeP₄₅₀-3A (CYP3A) isoforms, had a dose-reducing effect on thetherapeutically effective dose of the HIV protease inhibitor of formula(1).

HIV protease inhibitors of the present invention have the formula

wherein,

-   L is —C(═O)—, —O—C(═O)—, —NR¹⁰—C(═O)—, —O alkanediyl-C(═O)—,    —NR¹⁰-alkanediyl-C(═O)—, —C═S, —S(═O)₂—, —O—S(═O)₂—, —NR¹⁰—S(═O)₂    whereby either the C(═O) group or the S(═O)₂ group is attached to    the NR² moiety; wherein R¹⁰ is hydrogen, alkyl, alkenyl aralkyl,    cycloalkyl, cycloalkylalkyl, aryl, Het¹, Het¹alkyl, Het² or    Het²alkyl;-   R¹ is hydrogen, alkyl, alkenyl, alkynyl, alkanediyl alkylcarbonyl,    alkyloxy, alkyloxyalkyl, alkyloxycarbonyl alkanoyl, cycloalkyl,    cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkanoyl    cycloalkylalkoxycarbonyl, aryl, aralkyl, arylalkenyl, arylcarbonyl,    aryloxycarbonyl, aralkoxycarbonyl, aryloxyalkyl, haloalkyl,    hydroxyalkyl, aralkanoyl, aroyl, aryloxycarbonylalkyl,    aryloxyalkanoyl, Het¹, Het¹alkyl, Het¹oxy, Het¹oxyalkyl, Het¹aryl,    Het¹aralkyl, Het¹cycloalkyl, Het¹carbonyl, Het¹alkoxycarbonyl,    Het¹oxycarbonyl, Het¹alkanoyl, Het¹aralkanoyl, Het¹aryloxyalkyl,    Het¹aryloxycarbonyl, Het¹aralkoxycarbonyl, Het¹aroyl, Het², Het²oxy,    Het²alkyl; Het²oxyalkyl, Het²aralkyl, Het²cycloalkyl, Het²aryl,    Het²carbonyl, Het²oxycarbonyl, Het²alkanoyl, Het²alkoxycarbonyl,    Het²aralkanoyl, Het²aralkoxycarbonyl, Het²aryloxycarbonyl,    Het²aroyl, Het²aryloxyalkyl, aminocarbonyl, aminoalkanoyl,    aminoalkyl, optionally substituted by one or more substituents    independently selected from the group comprising alkyl, aralkyl,    aryl, Het¹, Het², cycloalkyl, alkyloxycarbonyl, carboxyl,    aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl,    alkylS(═O)_(t), hydroxy, cyano, halogen or amino optionally mono- or    disubstituted wherein the substituents are independently selected    from the group comprising alkyl, aryl, aralkyl, aryloxy, arylamino,    arylthio, aryloxyalkyl, arylaminoalkyl, aralkoxy, alkylthio, alkoxy,    aryloxyalkoxy, arylaminoalkoxy, aralkylamino, aryloxyalkylamino,    arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino,    aralkylthio, aryloxyalkylthio, arylaminoalkylthio,    arylthioalkylthio, alkylamino, cycloalkyl, cycloalkylalkyl, Het¹,    Het², Het¹alkyl, Het²alkyl, Het¹amino, Het²amino, Het¹alkylamino,    Het²alkylamino, Het¹thio, Het²thio, Het¹alkylthio, Het²alkylthio,    Het¹oxy and Het²oxy, OR⁷, SR⁷, SO₂NR⁷R⁸, SO₂N(OH)R⁷, CN, CR⁷═NR⁸,    S(O)R⁷, SO₂R⁷, CR⁷═N(OR⁸), N₃, NO₂, NR⁷R⁸, N(OH)R⁷, C(O)R⁷, C(S)R⁷,    CO₂R⁷, C(O)SR⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸, C(O)N(OH)R⁸, C(S)N(OH)R⁷,    NR⁷C(O)R⁸, NR⁷C(S)R⁸, N(OH)C(O)R⁷, N(OH)C(S)R⁷, NR⁷CO₂R⁸,    NR⁷C(O)NR⁸R⁹, and NR⁷C(S)NR⁸R⁹, N(OH)CO₂R⁷, NR⁷C(O)SR⁸,    N(OH)C(O)NR⁷R⁸, N(OH)C(S)NR⁷R⁸, NR⁷C(O)N(OH)R⁸, NR⁷C(S)N(OH)R⁸,    NR⁷SO₂R⁸, NHSO₂NR⁷R⁸, NR⁷SO₂NHR⁸, P(O)(OR⁷)(OR⁸), wherein t is an    integer selected from 1 or 2, R⁷, R⁸ and R⁹ are each independently    selected from the group comprising H, alkyl, alkenyl, and alkynyl;-   R² is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl,    alkyloxycarbonyl, aralkoxycarbonyl, alkylcarbonyl,    cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl    alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,    aryloxyalkanoyl, Het¹carbonyl, Het²carbonyl, Het¹oxycarbonyl,    Het²oxycarbonyl, Het¹alkanoyl, Het²alkanoyl, Het¹alkoxycarbonyl,    Het²alkoxycarbonyl, Het¹aralkanoyl, Het²aralkanoyl,    Het¹aralkoxycarbonyl, Het²aralkoxycarbonyl, Het¹aryloxycarbonyl,    Het²aryloxycarbonyl, Het¹aroyl, Het²aroyl, cycloalkyl, aryloxyalkyl,    Het¹aryloxyalkyl, Het²aryloxyalkyl, hydroxyalkyl, aminocarbonyl,    aminoalkanoyl, and mono- and disubstituted aminocarbonyl and mono-    and disubstituted aminoalkanoyl radicals wherein the substituents    are independently selected from the group comprising alkyl, aryl,    aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,    heterocycloalkyl, hetero cycloalkylalkyl radicals, or wherein said    aminoalkanoyl radical is disubstituted, said substituents along with    the nitrogen atom to which they are attached form a Het¹Het²,    Het¹aryl or Het²aryl radical;-   R³ is alkyl, aryl, cycloalkyl, cycloalkylalkyl, Het¹, Het²,    Het¹aryl, Het²aryl, or aralkyl optionally substituted with one or    more substituent independently selected from the group comprising    alkyl, halo, nitro, cyano, CF₃, —OR⁵, and —SR⁵, (CH₂)_(p)R⁶, OR⁷,    SR⁷, CN, N₃, C(O)R⁷, C(S)R⁷, CO₂R⁷, C(O)SR⁷, NR⁷R⁸, NR⁷C(O)R⁸,    NR⁷C(S)R⁸, NR⁷CO₂R⁸, C(O)NR⁷R⁸, C(S)NR⁷R⁸, and NR⁷C(O)SR⁸, wherein    R⁵ is a radical selected from the group comprising hydrogen and    alkyl, wherein: p is an integer from 0 to 5; R⁶ is cycloalkyl, Het¹,    aryl, or Het² in which at least one hydrogen atom is optionally    substituted with one or more substituents independently selected    from the group comprising a halogen, OH, OCH₃, NH₂, NO₂, SH, and CN,    wherein R⁷ and R⁸ have the same meaning as that defined above;-   R⁴ is hydrogen, alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or    di(alkyl)aminocarbonyl, cycloalkyl, cycloalkylalkyl, Het¹, Het²,    Het¹alkyl, Het²alkyl, Het¹cycloalkyl, Het²cycloalkyl, Het¹aryl,    Het²aryl, alkylthioalkyl, alkenyl, alkynyl, alkyloxyalkyl haloalkyl,    alkylsulfonylalkyl, hydroxyalkyl, aralkyl, aminoalkyl, or alkyl,    optionally substituted with one or more substituents independently    selected from comprising aryl, Het¹, Het², cycloalkyl,    alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or    di(alkyl)aminocarbonyl, aminosulfonyl, alkylS(═O)_(t), hydroxy,    cyano, nitro, thio, halogen or amino optionally mono- or    disubstituted wherein the substituents are independently selected    from the group comprising alkyl, aryl, aralkyl, cycloalkyl,    cycloalkylalkyl, Het¹, Het², Het¹alkyl and Het²alkyl.

The present invention also relates to the use of said combination as amedicament for the treatment, the prevention or for combating retroviralinfection. The present invention further relates to the use of saidcombination in the manufacture of a medicament for the treatment,prevention or for combating retroviral infection and in a method oftreatment for retroviral infection. The present invention also relatesto the use of said combination in high-throughput target-analyte assayssuch as, for example, phenotypic resistance monitoring assays.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients, as well as any productwhich results, directly or indirectly, from combination of the specifiedingredients.

Whenever the term “substituted” is used in defining the HIV proteaseinhibitor of formula (1), it is meant to indicate that one or morehydrogens on the atom indicated in the expression using “substituted” isreplaced with a selection from the indicated group, provided that theindicated atom's normal valency is not exceeded, and that thesubstitution results in a chemically stable compound, i.e. a compoundthat is sufficiently robust to survive isolation to a useful degree ofpurity from a reaction mixture, and formulation into a therapeuticagent.

As used herein, the term “halo” or “halogen” as a group or part of agroup is generic for fluoro, chloro, bromo or iodo.

The term “alkyl”, alone or in combination, means straight and branchedchained saturated hydrocarbon radicals containing from 1 to 10 carbonatoms, preferably from 1 to 8 carbon atoms, more preferably 1 to 6carbon atoms, and even more preferably 1 to 4 carbon atoms. Examples ofsuch radicals include methyl, ethyl, n-propyl, isopropyl n-butyl,isobutyl, set-butyl, tert-butyl, 2-methylbutyl, pentyl, iso-amyl hexyl,3-methylpentyl, octyl and the like.

The term “alkanediyl”, alone or in combination, defines bivalentstraight and branched chained saturated hydrocarbon radicals containingfrom 1 to 10 carbon atoms, preferably from 1 to 8 carbon atoms, morepreferably 1 to 6 carbon atoms and even more preferably 1 to 4 carbonatoms, such as, for example, methylene, ethan-1,2-diyl, propan-1,3-diyl,propan-1,2-diyl, butan-1,4-diyl, pentan-1,5-diyl, hexan-1,6-diyl,2-methylbutan-1,4-diyl, 3-methylpentan-1,5-diyl and the like.

The term “alkenyl”, alone or in combination, defines straight andbranched chained hydrocarbon radicals containing from 2 to about 18carbon atoms, interestingly 2 to about 10 carbon atoms, preferably from2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms and even morepreferably 1 to 4 carbon atoms, containing at least one double bond suchas, for example, ethenyl, propenyl, butenyl, pentenyl, hexenyl and thelike.

The term “alkynyl”, alone or in combination, defines straight andbranched chained hydrocarbon radicals having from 2 to 10 carbon atomscontaining at least one triple bond, more preferably from 2 to about 6carbon atoms and even more preferably 1 to 4 carbon atoms. Examples ofalkynyl radicals include ethynyl, propynyl, propargyl, butynyl,pentynyl, hexynyl and the like.

The term “cycloalkyl” alone or in combination, means a saturated orpartially saturated monocyclic, bicyclic or polycyclic alkyl radicalwherein each cyclic moiety contains from about 3 to about 8 carbonatoms, preferably from about 3 to about 7 carbon atoms, more preferablyfrom 3 to about 6 carbon atoms. Examples of monocyclic cycloalkylradicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclodecyl and the like. Examples of polycyclic cycloalkylradicals include decahydronaphthyl, bicyclo[5.4.0]undecyl, adamantyl,and the like.

The term “cycloalkylalkyl” means an alkyl radical as defined herein, inwhich at least one hydrogen atom on the alkyl radical is replaced by acycloalkyl radical as defined herein. Examples of such cycloalkylalkylradicals include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, 1-cyclopentylethyl, 1-cyclohexylethyl,2-cyclopentylethyl, 2-cyclohexylethyl, cyclobutylpropyl,cyclopentylpropyl, 3-cyclopentylbutyl, cyclohexylbutyl and the like.

The term “aryl” alone or in combination, is meant to include phenyl andnaphtyl which both may be optionally substituted with one or moresubstituents independently selected from alkyl, alkoxy, halogen,hydroxy, amino, nitro, cyano, haloalkyl, carboxy, alkoxycarbonyl,cycloalkyl, Het¹, amido, optionally mono- or disubstitutedaminocarbonyl, methylthio, methylsulfonyl, and phenyl optionallysubstituted with one or more substituents selected from C₁₋₆alkyl,C₁₋₆alkyloxy, halogen, hydroxy, optionally mono- or disubstituted amino,nitro, cyano, haloC₁₋₆alkyl, carboxyl, C₁₋₆alkoxycarbonyl,C₃₋₇cycloalkyl, Het¹, optionally mono- or disubstituted aminocarbonyl,methylthio and methylsulfonyl; whereby the optional substituents on anyamino function are independently selected from alkyl, alkyloxy, Het¹,Het¹alkyl, Het¹alkyl, Het¹oxy, Het¹oxyalkyl, phenyl, phenyloxy,phenyloxyalkyl phenylalkyl, alkyloxycarbonylamino, amino, and aminoalkylwhereby each of the amino groups may optionally be mono- or wherepossible di-substituted with alkyl. Examples of aryl includes phenyl,p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy)phenyl,3-methyl-4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 3-nitrophenyl,3-aminophenyl, 3-acetamidophenyl, 4-acetamidophenyl,2-methyl-3-acetamidophenyl, 2-methyl-3-aminophenyl,3-methyl-4-aminophenyl, 2-amino-3-methylphenyl,2,4-dimethyl-3-aminophenyl, 4-hydroxyphenyl, 3-methyl-4-hydroxyphenyl,1-naphthyl, 2-naphthyl, 3-amino-1-naphthyl, 2-methyl-3-amino-1-naphthyl,6-amino-2-naphthyl, 4,6-dimethoxy-2-naphthyl and the like.

The term “aralkyl” alone or in combination, means an alkyl as definedherein, wherein an alkyl hydrogen atom is replaced by an aryl as definedherein. Examples of aralkyl radicals include benzyl, phenethyl,methylphenylmethyl, 3-(2-naphthyl)-butyl, and the like.

As used herein, the term C(═O) forms a carbonyl moiety with the carbonatom to which it is attached.

The term “haloalkyl” alone or in combination, means an alkyl radicalhaving the meaning as defined above wherein one or more alkyl hydrogensare replaced with a halogen, preferably, chloro or fluoro atoms, morepreferably fluoro atoms. Examples of such haloalkyl radicals includechloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl,trifluoromethyl, 1,1,1-trifluoroethyl and the like.

The term “Het¹” alone or in combination are those groups defined as asaturated or partially unsaturated monocyclic, bicyclic or polycyclicheterocycle having preferably 3 to 12 ring members, more preferably 5 to10 ring members and more preferably 5 to 8 ring members, which containsone or more heteroatom ring members selected from nitrogen, oxygen orsulfur and which is optionally substituted on one or more carbon atomsby alkyl, alkyloxy, halogen, hydroxy, oxo, optionally mono- ordisubstituted amino, nitro, cyano, haloalkyl, carboxyl, alkoxycarbonyl,cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio,methylsulfonyl, aryl and a saturated or partially unsaturatedmonocyclic, bicyclic or tricyclic heterocycle having 3 to 12 ringmembers which contains one or more heteroatom ring members selected fromnitrogen, oxygen or sulfur and whereby the optional substituents on anyamino function are independently selected from alkyl, alkyloxy, Het²,Het²alkyl, Het²oxy, Het²oxyakyl, aryl, aryloxy, aryloxyalkyl, aralkyl,alkyloxycarbonylamino, amino, and aminoalkyl whereby each of the aminogroups may optionally be mono- or where possible disubstituted withalkyl.

The term “Het²” as a group or part of a group is defined as an aromaticmonocyclic, bicyclic or tricyclic heterocycle having preferably 3 to 12ring members, more preferably 5 to 10 ring members and more preferably 5to 6 ring members, which contains one or more heteroatom ring membersselected from nitrogen, oxygen or sulfur and which is optionallysubstituted on one or more carbon atoms by alkyl, alkyloxy, halogen,hydroxy, optionally mono- or disubstituted amino, nitro, cyano,haloalkyl, carboxyl, alkoxycarbonyl, cycloalkyl, optionally mono- ordisubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, Het¹ andan aromatic monocyclic, bicyclic or tricyclic heterocycle having 3 to 12ring members; whereby the optional substituents on any amino functionare independently selected from alkyl, alkyloxy, Het¹, Het¹alkyl,Het¹oxy, Het¹oxyakyl, aryl, aryloxy, aryloxyalkyl, aralkyl,alkyloxycarbonylamino, amino, and aminoalkyl whereby each of the aminogroups may optionally be mono- or where possible di-substituted withalkyl.

The term “alkoxy” or “alkyloxy”, alone or in combination, means an alkylether radical wherein the term alkyl is as defined above. Examples ofsuitable alkyl ether radicals include methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, hexanoxy andthe like.

The term “arylthioalkoxy” means alkoxy as defined herein, wherein analkyl hydrogen atom is replaced by an arylthio as defined herein.Examples of arylthioalkoxy radicals include 2-(phenylthio)-ethoxy, andthe like.

The term “alkanoyl”, alone or in combination, means an acyl radicalderived from an alkylcarboxylic acid, examples of which include acetyl,propionyl, butyryl, valeryl, 4-methylvaleryl, and the like.

The term “alkylamino” means an alkyl amine radical, wherein the term“alkyl” is defined as above. Examples of alkylamino radicals includemethylamino or NHCH₃, ethylamino or NHCH₂CH₃, n-propylamino,isopropylamino, n-butylamino, isobutylamino, sec-butylamino,tert-butylamino, n-hexylamino, and the like.

The term “dialkylamino” means a dialkyl amine radical, wherein the term“alkyl” is defined as above. Examples of dialkylamino radicals includedimethylamino or N(CH₃)₂, diethylamino or N(CH₂CH₃)₂, ethylmethylaminoor N(CH₃)(CH₂CH₃), di(n-propyl)amino, di-isopropylamino and the like.

The term “alkylthio” means an alkyl thioether radical, wherein the term“alkyl” is defined as above. Examples of alkylthio radicals includemethylthio (SCH₃), ethylthio (SCH₂CH₃), n-propylthio, isopropylthio,n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, n-hexylthio,and the like.

The term “arylthio” means an aryl thioether radical, wherein the term“aryl” is as defined herein. Examples of arylthio radicals includephenylthio and the like.

The term “aminoalkanoyl” means an acyl group derived from anamino-substituted alkylcarboxylic acid wherein the amino group can be aprimary, secondary or tertiary amino group containing substituentsselected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicalsand the like.

The term “aminocarbonyl” alone or in combination, means anamino-substituted carbonyl (carbamoyl) group wherein the amino group canbe a primary, secondary or tertiary amino group containing substituentsselected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicalsand the like.

The term “aralkanoyl” means an acyl radical derived from anaryl-substituted alkanecarboxylic acid such as phenylacetyl,3-phenylpropionyl(hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl,4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl,and the like.

The term “aralkoxy” means alkoxy as defined herein, wherein an alkylhydrogen atom is replaced by an aryl as defined herein. Examples ofaralkoxy radicals include 2-phenylethoxy, 2-phenyl-1-propoxy, and thelike.

The term “aralkoxycarbonyl”, alone or in combination, means a radical ofthe formula aralkyl-O—C(═O)— in which the term “aralkyl” has thesignificance given above. Examples of an aralkoxycarbonyl radical arebenzyloxycarbonyl and 4-methoxyphenylmethoxycarbonyl.

The term “aralkylamino” means alkylamino as defined herein, wherein analkyl hydrogen atom is replaced by an aryl as defined herein. Examplesof aralkylamino radicals include 2-phenethylamino,4-phenyl-n-butylamino, and the like.

The term “aralkylthio” means alkylthio as defined herein, wherein analkyl hydrogen atom is replaced by an aryl as defined herein. Examplesof aralkylthio radicals include 3-phenyl-2-propylthio,2-(2-naphthyl)-ethylthio, and the like.

The term “aroyl” means an acyl radical derived from an arylcarboxylicacid, aryl having the meaning given above. Examples of sucharylcarboxylic acid radicals include substituted and unsubstitutedbenzoic or naphthoic acid such as benzoyl, 4-chlorobenzoyl,4-carboxybenzoyl, 4-(benzyloxycarbonyl)benzoyl, 1-naphthoyl,2-naphthoyl, 6-carboxy-2 naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl,3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl,3-(benzyloxyformamidol-2-naphthoyl, and the like.

The term “arylaminoalkoxy” means alkoxy as defined herein, wherein analkyl hydrogen atom is replaced by an arylamino as defined herein.Examples of (arylamino) alkoxy radicals include 2-(phenylamino)-ethoxy,2-(2-naphthylamino)-1-butoxy, and the like.

The term “arylaminoalkyl” means alkyl as defined herein, wherein analkyl hydrogen atom is replaced by an arylamino as defined herein.Examples of arylaminoalkyl radicals include phenylaminoethyl,4-(3-methoxyphenylamino)-1-butyl, and the like.

The term “arylaminoalkylamino” means alkylamino as defined herein,wherein an alkyl hydrogen atom is replaced by an arylamino as definedherein. Examples of (arylamino) alkylamino radicals include3-(naphthylamino)-propylamino, 4-(phenylamino)-1-butylamino, and thelike.

The term “arylaminoalkylthio” means alkylthio as defined herein, whereinan alkyl hydrogen atom is replaced by an arylamino as defined herein.Examples of (arylamino)alkylthio radicals include2-(phenylamino)-ethylthio, 3-(2-naphthylamino)-n-propylthio, and thelike.

The term “aryloxy” means a radical of the formula aryl-O— in which theterm aryl has the significance given above.

The term “arylamino” means an amino radical, wherein an amino hydrogenis replaced by an aryl as defined herein.

The term “aryloxyalkanoyl” means an acyl radical of the formulaaryl-O-alkanoyl wherein aryl and alkanoyl have the meaning given above.

The term “aryloxyalkoxy” means alkoxy as defined herein, wherein analkyl hydrogen atom is replaced by an aryloxy as defined herein.Examples of (aryloxy) alkoxy radicals include 2-phenoxyethoxy,4-(3-aminophenoxy)-1-butoxy, and the like.

The term “aryloxyalkyl” means alkyl as defined herein, wherein an alkylhydrogen atom is replaced by an aryloxy as defined herein. Examples ofaryloxyalkyl radicals include phenoxyethyl, 4-(3-aminophenoxy)-1-butyl,and the like.

The term “aryloxyalkylamino” means alkylamino as defined herein, whereinan alkyl hydrogen atom is replaced by an aryloxy as defined herein.Examples of (aryloxy) alkylamino radicals include3-phenoxy-n-propylamino, 4-phenoxybutylamino, and the like.

The term “aryloxyalkylthio” means alkylthio as defined herein, whereinan alkyl hydrogen atom is replaced by an aryloxy as defined herein.Examples of (aryloxy) alkylthio radicals include 3-phenoxypropylthio, 4(2-fluorophenoxy)-butylthio, and the like.

The term “arylthioalkylamino” means alkylamino as defined herein,wherein an alkyl hydrogen atom is replaced by an arylthio as definedherein. Examples of (arylthio) alkylamino radicals include2-(phenylthio)-ethylamino, and the like.

The term “arylthioalkylthio” means alkylthio as defined herein, whereinan alkyl hydrogen atom is replaced by arylthio as defined herein.Examples of (arylthio) alkylthio radicals include2-(naphthylthio)-ethylthio, 3-(phenylthio)-propylthio, and the like.

The term “cycloalkylalkyl” means an alkyl, wherein an alkyl hydrogen isreplaced by a cycloalkyl as defind herein.

The term “cycloalkylalkoxycarbonyl” means an acyl group derived from acycloalkylalkoxycarboxylic acid of the formula cycloalkylalkyl-O—COOHwherein cycloalkylalkyl has the meaning given above.

The term “cycloalkylcarbonyl” means an acyl group derived from amonocyclic or bridged cycloalkanecarboxylic acid such ascyclopropylcarbonyl, cyclohexylcarbonyl, adamantylcarbonyl, and thelike, or from a benz-fused monocyclic cycloalkanecarboxylic acid whichis optionally substituted by one or more substituents selected fromalkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, haloalkyl,carboxy, alkoxycarbonyl, cycloalkyl, heterocycloalkyl, alkanoylamino,amido, mono and dialkyl substituted amino, mono and dialkyl substitutedamido and the like, such as 1,2,3,4-tetrahydro-2-naphthoyl,2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl.

The term “Het²alkoxy” means alkoxy as defined herein, wherein an alkylhydrogen atom is replaced by a Het² as defined herein. Examples ofHet²alkoxy radicals include 2-pyridylmethoxy, 4-(1-imidazolyl)-butoxy,and the like.

The term “Het²alkyl” means alkyl as defined herein, wherein an alkylhydrogen atom is replaced by a Het² as defined herein. Examples ofHet²alkyl radicals include 2-pyridylmethyl, 3-(4-thiazolyl)-propyl, andthe like.

The term “Het²alkylamino” means alkylamino as defined herein, wherein analkyl hydrogen atom is replaced by a Het² as defined herein. Examples ofHet²alkylamino radicals include 4-pyridylmethylamino, 3(2-furanyl)-propylamino, and the like.

The term “Het²alkylthio” means alkylthio as defined herein, wherein analkyl hydrogen atom is replaced by a Het² as defined herein. Examples ofHet²alkylthio radicals include 3-pyridylmethylthio, 3(4-thiazolyl)-propylthio, and the like.

The term “Het²amino” means Het² as defined herein, wherein a hydrogenatom on the Het² ring is replaced by a nitrogen. Het²amino radicalsinclude, for example, 4-thiazolylamino, 2-pyridylamino, and the like.

The term “Het²oxy” means Het² as defined herein, wherein a hydrogen atomon the Het² ring is replaced by an oxygen. Het²oxy radicals include, forexample, 4-pyridyloxy, 5-quinolyloxy, and the like.

The term “Het²oxycarbonyl” means an acyl radical derived from acarboxylic acid represented by Het²-O—COOH wherein Het² has the meaninggiven above.

The term “Het²thio” means Het² as defined herein, wherein a hydrogenatom on the Het² ring is replaced by a sulfur. Het²thio radicalsinclude, for example, 3-pyridylthio, 3-quinolylthio, 4-imdazolylthio,and the like.

The term “Het¹alkanoyl” is an acyl radical derived from aHet¹-substituted alkylcarboxylic acid wherein Het¹ has the meaning givenabove.

The term “Het¹oxycarbonyl” means an acyl radical derived from aHet¹-O—COOH wherein Het¹ has the meaning given above.

The term “alkylsulfonylalkyl” means an alkyl-S(═O)₂-alkyl radical,wherein “alkyl” is defined as above. Examples alkyl-S(═O)₂-alkylradicals include ethylsulfonylmethyl and the like.

The term “alkyloxyalkyl” means a radical of formula alkyl-O-alkyl,wherein alkyl is defined as above.

The term “alkyloxycarbonyl” means a radical of formula alkyl-O—C(O)—.Examples of alkyloxycarbonyl radicals include ethyloxycarbonyl,methyloxycarbonyl, n-propyloxycarbonyl.

The term “Het¹alkoxycarbonyl” means an alkyloxycarbonyl radical, whereinan alkyl hydrogen is replaced by a Het¹ radical, wherein Het¹ is asdefined herein.

The term “hydroxyalkyl” means an alkyl radical, as defined above,wherein one or more hydrogens are replaced with hydroxy. Examples ofhydroxyalkyl radical include hydroxymethyl, 2-hydroxy-n-propyl,3-hydroxybutyl, 2,3-dihydroxybutyl, dihydroxymethyl.

The term “alkylcarbonyl” means a radical of formula alkyl-C(═O)—,wherein alkyl has the meaning as defined above. Examples ofalkylcarbonyl radicals include, methylcarbonyl, ethylcarbonyl.

The term “cycloalkylalkanoyl” means an alkanoyl radical as definedherein, wherein at least one alkanoyl hydrogen is replaced by acycloalkyl radical, wherein cycloalkyl has the meaning as defined above.

The term “arylalkenyl” means an alkenyl radical as defined above,wherein at least one alkenyl hydrogen is replaced by an aryl radical,wherein aryl has the meaning as defined above.

The term “arylcarbonyl” means a radical of the formula aryl-C(═O)—,wherein aryl has the meaning as defined above.

The term “aryloxycarbonyl” means a radical of the formula aryl-O—C(═O)—,wherein aryl has the meaning as defined above.

The term “aryloxycarbonylalkyl” means an alkyl radical, as definedabove, wherein at least one alkyl hydrogen is replaced by anaryloxycarbonyl radical as defined above.

The term “Het¹oxyalkyl” means a radical of the formula Het¹-O-alkyl,wherein alkyl and Het¹ have the meaning as defined above.

The term “Het¹aryl” means an aryl radical, as defined above, wherein atleast one aryl hydrogen is replaced by Het¹, wherein Het¹ has themeaning as defined above.

The term “Het¹aralkyl” means an aralkyl radical as define above, whereinat least one aralkyl hydrogen is replaced by Het¹, wherein Het¹ has themeaning as defined above.

The term “Het¹cycloalkyl” means a cycloalkyl radical as defined above,wherein at least one cycloalkyl hydrogen is replaced by Het¹, whereinHet¹ has the meaning as defined above.

The term “Het¹carbonyl” means a radical of formula Het¹-C(═O)—, whereinHet¹ has the meaning as defined above.

The term “Het¹aralkanoyl” means an aralkanoyl radical as defined above,wherein at least one aryl hydrogen is replaced by Het¹, wherein Het¹ hasthe meaning as defined above.

The term “Het¹aryloxyalkyl” means an aryloxyalkyl radical as definedabove, wherein at least one aryl hydrogen is replaced by Het¹, whereinHet¹ has the meaning as defined above.

The term “Het¹aryloxycarbonyl” means an aryloxycarbonyl radical asdefined above, wherein at least one aryl hydrogen is replaced by Het¹,wherein Het¹ has the meaning as defined above.

The term “Het¹aralkoxycarbonyl” means an aralkoxycarbonyl radical asdefined herein, wherein at least one aryl hydrogen is replaced by Het¹,wherein Het¹ has the meaning as defined above.

The term “Het¹aroyl” means an aroyl radical as defined herein wherein atleast one aroyl hydrogen is replaced by Het¹, wherein Het¹ has themeaning as defined above.

The term “heteroaryl” means an aryl as defined herein wherein at leastone carbon atom is replaced by a heteroatom selected from the groupcomprising nitrogen, sulphur or oxygen.

The term “heteroaralkyl” means an alkyl as defined herein wherein atleast one alkyl hydrogen is replaced by an heteroaryl as defined herein.

The term “heterocycloalkyl” means an cycloalkyl as defined hereinwherein at least one carbon atom is replaced by a heteroatom selectedform the group comprising nitrogen, sulfur or oxygen.

The term “heterocycloalkylalkyl” means an alkyl as defined herein,wherein at least one alkyl hydrogen is replaced by a heterocycloalkyl asdefined herein.

As used herein “t” is an integer independently selected from 1 or 2,except if defined otherwise.

As used herein before, the term “one or more” covers the possibility ofall the available C-atoms, where appropriate, to be substituted,preferably, one, two or three. When any variable (e.g. halogen or alkyl)occurs more than one time in any constituent, each definition isindependent.

An interesting group of compounds of formula (I) for use in acombination with a cytochrome P₄₅₀ inhibitor are those compoundswherein,

-   L is —C(═O)—, —O—C(═O)—, —NR¹⁰—C(═O)—, —O-alkanediyl-C(═O)—,    —NR¹⁰-alkanediyl-C(═O)—, —C═S, —S(═O)₂—, —O—S(═O)₂—, —NR¹⁰—S(═O)₂    whereby either the C(═O) group or the S(═O)₂ group is attached to    the NR¹⁰ moiety; wherein R¹⁰ is hydrogen, alkyl alkenyl, aralkyl,    cycloalkyl, cycloalkylalkyl, aryl, Het¹, Het¹alkyl, Het² or    Het²alkyl;-   R¹ is hydrogen, alkyl, alkenyl, alkynyl, alkanediyl, alkylcarbonyl,    alkyloxy, alkyloxyalkyl, alkyloxycarbonyl, alkanoyl, cycloalkyl,    cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkanoyl,    cycloalkylalkoxycarbonyl, aryl, aralkyl, arylalkenyl, arylcarbonyl,    aryloxycarbonyl, aralkoxycarbonyl, aryloxyalkyl, haloalkyl,    hydroxyalkyl, aralkanoyl, aroyl, aryloxycarbonylalkyl,    aryloxyalkanoyl, Het¹, Het¹alkyl, Het¹oxy, Het¹oxyalkyl, Het¹aryl,    Het¹aralkyl, Het¹cycloalkyl, Het¹carbonyl, Het¹alkoxycarbonyl,    Het¹oxycarbonyl, Het¹alkanoyl, Het¹aralkanoyl, Het¹aryloxyalkyl,    Het¹aryloxycarbonyl, Het¹aralkoxycarbonyl, Het¹aroyl, Het², Het²oxy,    Het²alkyl; Het²oxyalkyl, Het²aralkyl, Het²cycloalkyl, Het²aryl,    Het²carbonyl, Het²oxycarbonyl, Het²alkanoyl, Het²alkoxycarbonyl,    Het²aralkanoyl, Het²aralkoxycarbonyl, Het²aryloxycarbonyl,    Het²aroyl, Het²aryloxyalkyl, aminocarbonyl, aminoalkanoyl,    aminoalkyl, optionally substituted by one or more substituents    independently selected from the group comprising alkyl, aralkyl,    aryl, Het¹, Het², cycloalkyl, alkyloxycarbonyl carboxyl,    aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl    alkylS(═O)_(t), hydroxy, cyano, halogen or amino optionally mono- or    disubstituted wherein the substituents are independently selected    from the group comprising alkyl, aryl, aralkyl, aryloxy, arylamino,    arylthio, aryloxyalkyl, arylaminoalkyl, aralkoxy, alkylthio, alkoxy,    aryloxyalkoxy, arylaminoalkoxy, aralkylamino, aryloxyalkylamino,    arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino,    aralkylthio, aryloxyalkylthio, arylaminoalkylthio,    arylthioalkylthio, alkylamino, cycloalkyl, cycloalkylalkyl, Het¹,    Het², Het¹alkyl, Het²alkyl, Het¹amino, Het²amino, Het¹alkylamino,    Het²alkylamino, Het¹thio, Het²thio, Het¹alkylthio, Het²alkylthio,    Het¹oxy and Het²oxy, OR⁷, SR⁷, SO₂NR⁷R⁸, SO₂N(OH)R⁷, CN, CR⁷═NR⁸,    S(O)R⁷, SO₂R⁷, CR⁷=N(OR⁸), N₃, NO₂, NR⁷R⁸, N(OH)R⁷, C(O)R⁷, C(S)R⁷,    CO₂R⁷, C(O)SR⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸, C(O)N(OH)R⁸, C(S)N(OH)R⁷,    NR⁷C(O)R⁸, NR⁷C(S)R⁸, N(OH)C(O)R⁷, N(OH)C(S)R⁷, NR⁷CO₂R⁸,    NR⁷C(O)NR⁸R⁹, and NR⁷C(S)NR⁸R⁹, N(OH)CO₂R⁷, NR⁷C(O)SR⁸,    N(OH)C(O)NR⁷R⁸, N(OH)C(S)NR⁷R⁸, NR⁷C(O)N(OH)R⁸, NR⁷C(S)N(OH)R⁸,    NR⁷SO₂R⁸, NHSO₂NR⁷R⁸, NR⁷SO₂NHR⁸, P(O)(OR⁷)(OR⁸), wherein t is an    integer between 1 and 2, R⁷, R⁸ and R⁹ are each independently    selected from the group comprising H, alkyl, alkenyl and alkynyl;-   R² is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl,    alkyloxycarbonyl aralkoxycarbonyl alkylcarbonyl, cycloalkylcarbonyl,    cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl,    aroyl, aryloxycarbonyl aryloxycarbonylalkyl, aryloxyalkanoyl,    Het¹carbonyl, Het²carbonyl, Het¹oxycarbonyl, Het²oxycarbonyl,    Het¹alkanoyl, Het²alkanoyl, Het¹alkoxycarbonyl, Het²alkoxycarbonyl,    Het¹aralkanoyl, Het²aralkanoyl, Het¹aralkoxycarbonyl,    Het²aralkoxycarbonyl, Het¹aryloxycarbonyl, Het²aryloxycarbonyl,    Het¹aroyl, Het²aroyl, cycloalkyl, aryloxyalkyl, Het¹aryloxyalkyl,    Het²aryloxyalkyl, hydroxyalkyl, aminocarbonyl, aminoalkanoyl, and    mono- and disubstituted aminocarbonyl and mono- and disubstituted    aminoalkanoyl radicals wherein the substituents are independently    selected from the group comprising alkyl, aryl, aralkyl, cycloalkyl,    cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, hetero    cycloalkylalkyl radicals, or wherein said aminoalkanoyl radical is    disubstituted, said substituents along with the nitrogen atom to    which they are attached form a Het¹, Het², Het¹aryl or Het²aryl    radical;-   R³ is alkyl aryl, cycloalkyl, cycloalkylalkyl, Het¹, Het², Het¹aryl,    Het²aryl, or aralkyl optionally substituted with one or more    substituent independently selected from the group comprising alkyl,    halo, nitro, cyano, CF₃, —OR⁵, and —SR⁵, (CH₂)_(p)R⁶, OR⁷, SR⁷, CN,    N₃, C(O)R⁷, C(S)R⁷, CO₂R⁷, C(O)SR⁷, NR⁷R⁸, NR⁷C(O)R⁸, NR⁷C(S)R⁸,    NR⁷CO₂R⁸, C(O)NR⁷R⁸, C(S)NR⁷R⁸, and NR⁷C(O)SR⁸, wherein R⁵ is a    radical selected from the group comprising hydrogen and alkyl,    wherein: p is an integer from 0 to 5; R⁶ is cycloalkyl, Het¹, aryl,    or Het² in which at least one hydrogen atom is optionally    substituted with one or more substituents independently selected    from the group comprising a halogen, OH, OCH₃, NH₂, NO₂, SH, and CN,    wherein R⁷ and R⁸ have the same meaning as that defined above;-   R⁴ is hydrogen, alkyloxycarbonyl, carboxyl, aminocarbonyl mono- or    di(alkyl)aminocarbonyl, cycloalkyl, cycloalkylalkyl, Het¹, Het²,    Het¹alkyl, Het²alkyl, Het¹cycloalkyl, Het²cycloalkyl, Het¹aryl,    Het²aryl, alkylthioalkyl alkenyl, alkynyl, alkyloxyalkyl, haloalkyl,    alkylsulfonylalkyl, hydroxyalkyl, aralkyl, aminoalkyl, or alkyl,    optionally substituted with one or more substituents independently    selected from comprising aryl, Het¹, Het², cycloalkyl,    alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or    di(alkyl)aminocarbonyl, aminosulfonyl, alkylS(═O)_(t), hydroxy,    cyano, nitro, thio, halogen or amino optionally mono- or    disubstituted wherein the substituents are independently selected    from the group comprising alkyl, aryl, aralkyl, cycloalkyl,    cycloalkylalkyl, Het¹, Het², Het¹alkyl and Het²alkyl.

Another interesting subgroup of compounds of formula (1) for use in acombination with a cytochrome P₄₅₀ inhibitor are those compoundswherein,

-   L is —C(═O)—, -alkanediyl-C(═O)—, whereby the C(═O) group is    attached to the NR² moiety; wherein R¹⁰ is hydrogen, alkyl, alkenyl,    aralkyl, cycloalkyl, cycloalkylalkyl aryl, Het¹, Het¹alkyl, Het² or    Het²alkyl;-   R¹ is hydrogen, alkyl, alkenyl, alkynyl, alkanediyl, alkylcarbonyl,    alkyloxy, alkyloxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl    arylalkenyl, aryloxyalkyl, haloalkyl, hydroxyalkyl,    aryloxycarbonylalkyl, aryloxyalkanoyl, Het¹, Het¹alkyl, Het¹oxy,    Het¹oxyalkyl, Het¹aryl, Het¹aralkyl, Het¹cycloalkyl,    Het¹aryloxyalkyl, Het², Het²oxy, Het²alkyl, Het²oxyalkyl,    Het²aralkyl, Het²cycloalkyl, Het²aryl, Het²aryloxyalkyl,    aminocarbonyl, aminoalkanoyl, aminoalkyl, optionally substituted by    one or more substituents independently selected from the group    comprising alkyl, aralkyl, aryl, Het¹, Het², cycloalkyl,    alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or    di(alkyl)aminocarbonyl, aminosulfonyl, alkylS(═O)_(t), hydroxy,    cyano, halogen or amino optionally mono- or disubstituted wherein    the substituents are independently selected from the group    comprising alkyl, aryl, aralkyl, aryloxy, arylamino, arylthio,    aryloxyalkyl, arylaminoalkyl, aralkoxy, alkylthio, alkoxy,    aryloxyalkoxy, arylaminoalkoxy, aralkylamino, aryloxyalkylamino,    arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino,    aralkylthio, aryloxyalkylthio, arylaminoalkylthio,    arylthioalkylthio, alkylamino, cycloalkyl, cycloalkylalkyl, Het¹,    Het², Het¹alkyl, Het²alkyl, Het¹amino, Het²amino, Het¹alkylamino,    Het²alkylamino, Het¹thio, Het²thio, Het¹alkylthio, Het²alkylthio,    Het¹oxy and Het²oxy, OR⁷, SR⁷, SO₂NR⁷R⁸, SO₂N(OH)R⁷, CN, CR⁷═NR⁸,    S(O)R⁷, SO₂R⁷, CR⁷═N(OR⁸), N₃, NO₂, NR⁷R⁸, N(OH)R⁷, C(O)R⁷, C(S)R⁷,    CO₂R⁷, C(O)SR⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸, C(O)N(OH)R⁸, C(S)N(OH)R⁷,    NR⁷C(O)R⁸, NR⁷C(S)R⁸, N(OH)C(O)R⁷, N(OH)C(S)R⁷, NR⁷CO₂R⁸,    NR⁷C(O)NR⁸R⁹, and NR⁷C(S)NR⁸R⁹, N(OH)CO₂R⁷, NR⁷C(O)SR⁸,    N(OH)C(O)NR⁷R⁸, N(OH)C(S)NR⁷R⁸, NR⁷C(O)N(OH)R⁸, NR⁷C(S)N(OH)R⁸,    NR⁷SO₂R⁸, NHSO₂NR⁷R⁸, NR⁷SO₂NHR⁸, P(O)(OR⁷)(OR⁸), wherein t is an    integer independently selected from 1 or 2, R⁷, R⁸ and R⁹ are each    independently selected from the group comprising H, alkyl, alkenyl,    and alkynyl;-   R² is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl,    alkyloxycarbonyl, aralkoxycarbonyl, alkylcarbonyl,    cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl,    alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,    aryloxyalkanoyl, Het¹carbonyl, Het²carbonyl, Het¹oxycarbonyl,    Het²oxycarbonyl, Het¹alkanoyl, Het²alkanoyl, Het¹alkoxycarbonyl,    Het²alkoxycarbonyl, Het¹aralkanoyl, Het²aralkanoyl,    Het¹aralkoxycarbonyl, Het²aralkoxycarbonyl, Het¹aryloxycarbonyl,    Het²aryloxycarbonyl, Het¹aroyl, Het²aroyl, cycloalkyl, aryloxyalkyl,    Het¹aryloxyalkyl, Het²aryloxyalkyl, hydroxyalkyl, aminocarbonyl,    aminoalkanoyl, and mono- and disubstituted aminocarbonyl and mono-    and disubstituted aminoalkanoyl radicals wherein the substituents    are independently selected from the group comprising alkyl, aryl,    aralkyl, cycloalkyl, cycloalkylalkyl, Het², Het²alkyl, Het¹,    Het¹alkyl radicals, or wherein said aminoalkanoyl radical is    disubstituted, said substituents along with the nitrogen atom to    which they are attached form a Het¹, Het², Het¹aryl or Het²aryl    radical;-   R³ is alkyl, aryl, cycloalkyl, cycloalkylalkyl, Het¹, Het²,    Het¹aryl, Het²aryl, or aralkyl, optionally substituted with one or    more substituent independently selected from the group comprising    alkyl, halo, nitro, cyano, CF₃, —OR⁵, and —SR⁵, (CH₂)_(p)R⁶, OR⁷,    SR⁷, CN, N₃, C(O)R⁷, C(S)R⁷, CO₂R⁷, C(O)SR⁷, NR⁷R⁸, NR⁷C(O)R⁸,    NR⁷C(S)R⁸, NR⁷CO₂R⁸, C(O)NR⁷R⁸, C(S)NR⁷R⁸, and NR⁷C(O)SR⁷; wherein    R⁵ is a radical selected from the group comprising hydrogen and    alkyl; wherein p is an integer from 0 to 5; R⁶ is cycloalkyl, Het¹,    aryl, or Het² in which at least one hydrogen atom is optionally    substituted with one or more substituents independently selected    from the group comprising a halogen, OH, OCH₃, NH₂, NO₂, SH, and CN,    wherein R⁷ and R⁸ have the same meaning as that defined above;-   R⁴ is hydrogen, alkyloxycarbonyl carboxyl, aminocarbonyl, mono- or    di(alkyl)aminocarbonyl, cycloalkyl, cycloalkylalkyl, Het¹, Het²,    Het¹alkyl, Het²alkyl, Het¹cycloalkyl, Het²cycloalkyl, Het¹aryl,    Het²aryl, alkylthioalkyl, alkenyl, alkynyl, alkyloxyalkyl,    haloalkyl, alkylsulfonylalkyl hydroxyalkyl, aralkyl, aminoalkyl, or    alkyl, optionally substituted with one or more substituents    independently selected from comprising aryl, Het¹, Het², cycloalkyl,    alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or    di(alkyl)aminocarbonyl, aminosulfonyl, alkylS(═O)_(t), hydroxy,    cyano, nitro, thio, halogen or amino optionally mono- or    disubstituted wherein the substituents are independently selected    from the group comprising alkyl, aryl, aralkyl, cycloalkyl,    cycloalkylalkyl, Het¹, Het², Het¹alkyl and Het²alkyl.

According to an embodiment, the present invention relates to acombination comprising (a) a HIV protease inhibitor of formula (2) or apharmaceutically acceptable salt or ester thereof and (b) an inhibitorof cytochrome P₄₅₀,

wherein,

-   R¹ is hydrogen, alkyl, alkenyl, alkynyl, alkanediyl, alkylcarbonyl,    alkyloxy, alkyloxyalkyl, alkyloxycarbonyl, alkanoyl, cycloalkyl,    cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkanoyl,    cycloalkylalkoxycarbonyl, aryl, aralkyl, arylalkenyl, arylcarbonyl,    aryloxycarbonyl, aralkoxycarbonyl, aryloxyalkyl, haloalkyl,    hydroxyalkyl, aralkanoyl, aroyl, aryloxycarbonylalkyl,    aryloxyalkanoyl, Het¹, Het¹alkyl, Het¹oxy, Het¹oxyalkyl, Het¹aryl,    Het¹aralkyl, Het¹cycloalkyl, Het¹carbonyl, Het¹alkoxycarbonyl,    Het¹oxycarbonyl, Het¹alkanoyl, Het¹aralkanoyl, Het¹aryloxyalkyl,    Het¹aryloxycarbonyl, Het¹aralkoxycarbonyl, Het¹aroyl, Het², Het²oxy,    Het²alkyl; Het²oxyalkyl, Het²aralkyl, Het²cycloalkyl, Het²aryl,    Het²carbonyl, Het²oxycarbonyl, Het²alkanoyl, Het²alkoxycarbonyl,    Het²aralkanoyl, Het²aralkoxycarbonyl, Het²aryloxycarbonyl,    Het²aroyl, Het²aryloxyalkyl, aminocarbonyl, aminoalkanoyl,    aminoalkyl, optionally substituted by one or more substituents    independently selected from the group comprising alkyl, arylalkyl,    aryl, Het¹, Het², cycloalkyl, alkyloxycarbonyl, carboxyl,    aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl,    alkylS(═O)_(t), hydroxy, cyano, halogen or amino optionally mono- or    disubstituted wherein the substituents are independently selected    from the group comprising alkyl, aryl, aralkyl, aryloxy, arylamino,    arylthio, aryloxyalkyl, arylaminoalkyl, aralkoxy, alkylthio, alkoxy,    aryloxyalkoxy, arylaminoalkoxy, aralkylamino, aryloxyalkylamino,    arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino,    aralkylthio, aryloxyalkylthio, arylaminoalkylthio,    arylthioalkylthio, alkylamino, cycloalkyl, cycloalkylalkyl, Het¹,    Het², Het¹alkyl, Het²alkyl, Het¹amino, Het²amino, Het¹alkylamino,    Het²alkylamino, Het¹thio, Het²thio, Het¹alkylthio, Het²alkylthio,    Het¹oxy and Het²oxy, wherein t is an integer between 1 and 2.-   R² is hydrogen or alkyl;-   R³ is alkyl, aryl, cycloalkyl, cycloalkylalkyl, or aralkyl radical;-   R⁴ is hydrogen, alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or    di(alkyl)aminocarbonyl, cycloalkyl, alkenyl, alkynyl, or alkyl,    optionally substituted with one or more substituents independently    selected from the group comprising aryl, Het¹, Het², cycloalkyl,    alkyloxycarbonyl carboxyl, aminocarbonyl, mono- or    di(alkyl)aminocarbonyl, aminosulfonyl, alkylS(═O)_(t), hydroxy,    cyano, halogen or amino optionally mono- or disubstituted wherein    the substituents are independently selected from the group    comprising alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, Het¹,    Het², Het¹alkyl and Het²alkyl.

According to another embodiment, the present invention relates to acombination comprising (a) an HIV protease inhibitor of formula (3) or apharmaceutically acceptable salt or ester thereof and (b) an inhibitorof cytochrome P₄₅₀,

wherein,

-   R¹ is cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl,    cycloalkylalkanoyl, cycloalkylalkoxycarbonyl, aryl, aralkyl,    arylalkenyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl,    aryloxyalkyl, haloalkyl, hydroxyalkyl, aralkanoyl, aroyl,    aryloxycarbonylalkyl, aryloxyalkanoyl, Het¹, Het¹alkyl, Het¹oxy,    Het¹oxyalkyl, Het¹aryl, Het¹aralkyl, Het¹cycloalkyl, Het¹carbonyl,    Het¹alkoxycarbonyl, Het¹oxycarbonyl, Het¹alkanoyl, Het¹aralkanoyl,    Het¹aryloxyalkyl, Het¹, Het¹aralkoxycarbonyl, Het¹, Het², Het²oxy,    Het²alkyl; Het²oxyalkyl, Het²aralkyl, Het²cycloalkyl, Het²aryl,    Het²carbonyl, Het²oxycarbonyl, Het²alkanoyl, Het²alkoxycarbonyl,    Het²alkanoyl, Het²aralkoxycarbonyl, Het²aryloxycarbonyl, Het²aroyl,    Het²aryloxyalkyl, optionally substituted by one or more substituents    independently selected from the group comprising alkyl, aralkyl,    aryl, Het¹, Het², cycloalkyl, alkyloxycarbonyl, carboxyl,    aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl,    alkylS(═O)_(t), hydroxy, cyano, halogen or amino optionally mono- or    disubstituted wherein the substituents are independently selected    from the group comprising alkyl, aryl, aralkyl, aryloxy, arylamino,    arylthio, aryloxyalkyl, arylaminoalkyl, aralkoxy, alkylthio, alkoxy,    aryloxyalkoxy, arylaminoalkoxy, aralkylamino, aryloxyalkylamino,    arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino,    aralkylthio, aryloxyalkylthio, arylaminoalkylthio,    arylthioalkylthio, alkylamino, cycloalkyl, cycloalkylalkyl, Het¹,    Het², Het¹alkyl, Het²alkyl, Het¹amino, Het²amino, Het¹alkylamino,    Het²alkylamino, Het¹thio, Het²thio, Het¹alkylthio, Het²alkylthio,    Het¹oxy and Het²oxy, wherein t is an integer between 1 and 2.-   R⁴ is alkyl, optionally substituted with one or more substituent    independently selected from the group comprising aryl, Het¹, Het²,    cycloalkyl, and amino optionally mono- or disubstituted wherein the    substituents are independently selected from the group comprising    alkyl, aryl, Het¹, Het².

In one embodiment, the hexahydrofuro[2,3-b]furanyl group is of formula(5) having the (3R,3aS,6aR) stereochemistry.

According to yet another embodiment the present invention relates to acombination comprising (a) an HIV protease inhibitor as depicted inTable A, B, C, D or E or a pharmaceutically acceptable salt or esterthereof and (b) an inhibitor of cytochrome P₄₅₀.

Interesting combinations include combinations comprising (a) an HIVprotease inhibitor of formula (4) or a pharmaceutically acceptable saltor ester thereof and (b) an inhibitor of cytochrome P₄₅₀,

Other combinations of interest, include combinations wherein saidinhibitor of cytochrome P₄₅₀ is another HIV protease inhibitor and isfor example selected from the group comprising ritonavir, indinavir,nelfinavir, saquinavir, amprenavir, lopinavir, lasinavir, palinavir,telinavir, tipranavir, mozenavir, atazanavir and pharmaceuticallyacceptable salts and esters thereof. More in particular, said inhibitormay be selected from the group comprising ritonavir, amprenavir,nelfinavir or a pharmaceutically acceptable salt or ester thereof.

In general, combinations of two compounds can act synergistically, in anadditive way or antagonistically. Synergy between the two inhibitorswould mean a more potent combination therapy, without increasingundesired side effects. For the current invention, this was assessed inan experimental setting where the potency of different ratios of the twoHIV-protease inhibitors is measured. Results were plotted in anisobologram graph according to the method described by Chou and Talalay(Adv. Enzyme Regul. 22: 27-55, 1984). Antagonism on the contrary wouldpreclude the combination and restrict the area of use. The effects of acombination of a compound of formula (4) in combination with each of thecurrently approved HIV protease inhibitors are described in the examplesbelow (see example 3). The compound of formula (4) in combination withcurrently approved HIV protease inhibitors exhibits no antagonism. Atall molar ratios the compound of formula (4) shows synergy withamprenavir, nelfinavir and ritonavir and it shows additive inhibitionwith indinavir and saquinavir.

Other useful inhibitors of cytochrome P₄₅₀ include ketoconazole,cimetidine or bergamottin. Another group of cytochrome P₄₅₀ inhibitorsinclude itraconazole, clarithromycine, erythromycine, nefazodone,delavirdine or troleandomycine.

In one embodiment, the present invention relates to a combinationcomprising (a) an HIV protease inhibitor of formula (4) or apharmaceutically acceptable salt or ester thereof and (b) ritonavir or apharmaceutically acceptable salt or ester thereof. Said HIV proteaseinhibitor of formula (4) is carbamic acid[(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ylester.

Ritonavir is an inhibitor of P₄₅₀ 3A4 cytochrome. Cytochrome P₄₅₀ (CYP)3A4 oxidizes a broad spectrum of drugs by a number of metabolicprocesses. When ritonavir is given in combination with an HIV proteaseinhibitor of formula (1) such as the compound of formula (4), itincreases the trough concentrations (C_(min)) of such HIV proteaseinhibitor of formula (1) allowing reduction of the dose and dosingfrequency.

Whenever used hereinafter, the term “HIV protease inhibitors of formula(1)” or similar term is meant to include the compounds of generalformula (1), or any subgroup thereof, the compounds as depicted in TableA, B, C, D or E, their N-oxides, salts, stereoisomeric forms, racemicmixtures, pro-drugs, esters and metabolites, as well as theirquaternized nitrogen analogues. The N-oxide forms of said compounds aremeant to comprise compounds wherein one or several nitrogen atoms areoxidized to the so-called N-oxide.

The term “pro-drug” as used herein means the pharmacologicallyacceptable derivatives such as esters, amides and phosphates, such thatthe resulting in vivo biotransformation product of the derivative is theactive drug. The reference by Goodman and Gilman (The PharmacologicalBasis of Therapeutics, 8th Ed, McGraw-Hill, Int. Ed. 1992,“Biotransformation of Drugs”, p 13-15) describing pro-drugs generally ishereby incorporated. Pro-drugs of the components comprised in thecompositions of the invention can be prepared by modifying functionalgroups present in said component in such a way that the modificationsare cleaved, either in routine manipulation or in vivo, to the parentcomponent. Typical examples of pro-drugs are described for instance inWO 99/33795, WO 99/33815, WO 99/33793 and WO 99/33792 all incorporatedherein by reference. Pro-drugs are characterized by improved aqueoussolubility, increased bioavailability and are readily metabolized intothe active inhibitors in vivo.

The HIV protease inhibitors of formula (1) according to the inventionmay also exist in their tautomeric forms. Such forms, although notexplicitly indicated in the compounds described herein, are intended tobe included within the scope of the present invention.

The term stereochemically isomeric forms of the compounds of generalformula (1) defines all possible compounds made up of the same atomsbonded by the same sequence of bonds but having differentthree-dimensional structures which are not interchangeable, which thecompounds of the present invention may possess. Unless otherwisementioned or indicated, the chemical designation of a compound hereinencompasses the mixture of all possible stereochemically isomeric formswhich said compound may possess. Said mixture may contain alldiastereomers and/or enantiomers of the basic molecular structure ofsaid compound. All stereochemically isomeric forms of the components ofa composition according to the invention either in pure form or inadmixture with each other are intended to be embraced within the scopeof the present invention.

For therapeutic use, the salts of the components comprised in acombination according to the invention, are those wherein the counterionis pharmaceutically or physiologically acceptable.

The pharmaceutically acceptable salts of the components comprised in thecombinations of the present invention (in the form of water-,oil-soluble, or dispersible products) include the conventional non-toxicsalts or the quaternary ammonium salts which are formed, e.g., frominorganic or organic acids or bases. Examples of such acid additionsalts include acetate, adipate, alginate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, phosphate,propionate, succinate, sulphate, tartrate, thiocyanate, tosylate, andundecanoate. Base salts include ammonium salts, alkali metal salts suchas sodium and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases such asdicyclohexylamine salts, N-methyl-D-glucamine, and salts with aminoacids such a sarginine, lysine, and so forth. Also, the basicnitrogen-containing groups may be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl,and diamyl sulfates; long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides; aralkyl halides like benzyland phenethyl-bromides and others. Other pharmaceutically acceptablesalts include the sulfate salt ethanolate and sulfate salts.

The pharmaceutically acceptable salts of the components of the presentcombinations include the combination wherein one of the individualcomponents is in the form of a pharmaceutically acceptable salt, thecombination wherein all of the individual components are in the form ofpharmaceutically acceptable salts, the combination wherein one or moreof the individual components is in the form of a pharmaceuticallyacceptable salt while other of the components are used as the free base,or a pharmaceutically acceptable salt of the combined components (i.e.,a salt of the combination). The pharmaceutically acceptable esters ofthe HIV protease inhibitors of formula (1) according to the inventionrefer to non-toxic esters, preferably the alkyl esters such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl esters, of whichthe methyl ester is preferred. However, other esters such asphenyl-alkyl may be employed if desired.

Furthermore, the present invention relates to a pharmaceuticalcomposition comprising a therapeutic amount of a combination accordingto the invention and a pharmaceutically acceptable excipient. More inparticular, the present invention relates to a pharmaceuticalcomposition comprising (a) a therapeutically effective amount of an HIVprotease inhibitor of formula (1) and (b) a therapeutically effectiveamount of an inhibitor of cytochrome P₄₅₀, and (c) a pharmaceuticallyacceptable excipient.

According to an embodiment the present invention relates to apharmaceutical composition comprising (a) a therapeutically effectiveamount of an HIV protease inhibitor of formula (1) or any subgroupthereof such as the compound of formula (4) and (b) a therapeuticallyeffective amount of an inhibitor of cytochrome P₄₅₀, such as ritonavirand (c) a pharmaceutically acceptable excipient.

The pharmaceutical composition can be prepared in a manner known per seto one of skill in the art. For this purpose, at least one of an HIVprotease inhibitor of formula (1) or any subgroup thereof, and aninhibitor of cytochrome P₄₅₀, together with one or more solid or liquidpharmaceutical excipients and, if desired, in combination with otherpharmaceutical active compounds, are brought into a suitableadministration form or dosage form which can then be used as apharmaceutical in human medicine or veterinary medicine.

The term “therapeutically effective amount” as used herein means thatamount of active compound or component or pharmaceutical agent thatelicits the biological or medicinal response in a tissue, system animalor human that is being sought, in the light of the present invention, bya researcher, veterinarian, medical doctor or other clinician, whichincludes alleviation of the symptoms of the disease being treated. Sincethe instant invention refers to combinations comprising two or moreagents, the “therapeutically effective amount” is that amount of theagents taken together so that the combined effect elicits the desiredbiological or medicinal response. For example, the therapeuticallyeffective amount of a composition comprising (a) the compound of formula(4) and (b) ritonavir would be the amount of the compound of formula (4)and the amount of ritonavir that when taken together have a combinedeffect that is therapeutically effective.

According to the instant invention “a dose reducing effect on thetherapeutically effective dose” means the effect of an inhibitor ofcytochrome P₄₅₀ on the amount of a compound of formula (1) needed toelicit a therapeutic effect. It is an object of the instant inventionthat when an inhibitor of cytochrome P₄₅₀ is administered to a mammal inaddition to a compound of formula (1), the inhibitor of cytochrome P₄₅₀reduces the dose of the compound of formula (1) needed to elicit itstherapeutic effect, when compared to the sole administration of saidcompound of formula (1).

Due to the favorable pharmacological properties of the combinations ofthe present invention, particularly its activity against retroviralprotease enzymes, and more particularly its activity against multi-drugresistant HIV protease enzymes, said combination is useful in thetreatment of individuals infected by HIV and for the prophylaxis ofthese individuals.

An advantage of the combination of the present invention is that theminimal concentrations of the compound of formula (1) are increasedcompared to the sole administration of said compound. If an HIVinhibitor is present in a concentration which does not preventreplication of the HIV virus, mutants of the HIV virus may emerge. It isknown in the art that mutants of the HIV protease confer resistance toHIV protease inhibitors. Examples of such mutations comprise thosemutations, independently selected from the list comprising mutations atamino acid positions 10, 20, 24, 30, 32, 33, 36, 46, 47, 48, 50, 53, 54,63, 71, 73, 77, 82, 84, 88 or 90 in the HIV protease. The combination ofthe present invention may be useful to prevent or delay the onset ofmutations in HIV protease, or if the HIV protease contains mutations atthe initiation of therapy may prevent or delay the occurrence ofadditional mutations in the HIV protease.

It was now found that the combination of a compound of formula (1)together with an inhibitor of cytochrome P₄₅₀ resulted in a reducedincidence of adverse effects. Thus, it was now found that thecombination of a compound of formula (1) together with an inhibitor ofcytochrome P₄₅₀ has an improved safety and tolerability when compared towhen the compound of formula (1) is administered alone.

The term “individual,” as used herein refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

Alternatively, the combinations of the present invention may also beformulated as a combined preparation for simultaneous, separate orsequential use in HIV therapy. In such a case, the compound of generalformula (1) is formulated in a pharmaceutical composition containingother pharmaceutically acceptable excipients, and the inhibitor ofcytochrome P₄₅₀ is formulated separately in a pharmaceutical compositioncontaining other pharmaceutically acceptable excipients. Conveniently,these two separate pharmaceutical compositions can be part of a kit forsimultaneous, separate or sequential use.

Thus, the individual components of the combination of the presentinvention can be administered separately at different times during thecourse of therapy or concurrently in divided or single combinationforms. The present invention is therefore to be understood as embracingall such regimes of simultaneous or alternating treatment and the term“administering” is to be interpreted accordingly.

The present invention further relates to the use of a combinationaccording to the invention, in the treatment of individuals infected bya retrovirus and for the prophylaxis of these individuals. Theprophylaxis treatment can be advantageous in cases where an individualhas been subjected to a high risk of exposure to a virus, as can occurwhen individual has been in contact with an infected individual wherethere is a high risk of viral transmission. As an example, prophylacticadministration of said composition would be advantageous in a situationwhere a health care worker has been exposed to blood from anHIV-infected individual, or in other situations where an individualengaged in high-risk activities that potentially expose that individualto the HIV virus.

In general, the combinations of the present invention may be useful inthe treatment of warm-blooded animals infected with viruses whoseexistence is mediated by, or depends upon, a retroviral protease enzyme,in particular the HIV protease enzyme. Conditions which may be preventedor treated with the compositions of the present invention, especiallyconditions associated with HIV and other pathogenic retroviruses,include AIDS, AIDS-related complex (ARC), progressive generalizedlymphadenopathy (PGL), as well as chronic CNS diseases caused byretroviruses, such as, for example HIV mediated dementia and multiplesclerosis.

The combinations of the present invention may therefore be used asmedicaments against above-mentioned conditions. Said use as a medicineor method of treatment comprises the systemic administration toHIV-infected subjects of an amount effective to combat the conditionsassociated with HIV and other pathogenic retroviruses, especially HIV-1.Consequently, the combinations of the present invention can be used inthe manufacture of a medicament useful for treating, preventing orcombating infection or disease associated with retrovirus infection in amammal, in particular for treating conditions associated with HIV andother pathogenic retroviruses, more in particular medicaments useful fortreating patients infected with multi-drug resistant HIV virus.

The present invention further relates to the use of a combinationaccording to the invention in the manufacture of a medicament forinhibiting a protease of a retrovirus in a mammal infected with saidretrovirus. The present invention also relates to the use of acombination according to the invention in the manufacture of amedicament for inhibiting retroviral replication, in particular, whenthe retrovirus is a human immunodeficiency virus (HIV) and more inparticular when the retrovirus is a multidrug-resistant retrovirus.

The present invention further encompasses a report comprisinginformation obtained in any of the above described uses of a combinationaccording to the invention.

Treating AIDS or preventing or treating infection by HIV is defined asincluding, but not limited to, treating a wide range of states of HIVinfection: AIDS, ARC, both symptomatic and asymptomatic, and actual orpotential exposure to HIV. The compositions of the present are alsouseful for treating progressive generalized lymphadenophaty, Kaposi'ssyndrome, thrombocytopenia purpurea, AIDS-related neurologicalconditions such as AIDS dementia complex, multiple sclerosis, tropicalparapesis, and also anti-HIV antibody positive and HIV-positiveconditions, including such conditions in asymptomatic patients. Forexample, the combinations of this invention are useful in treatinginfection by HIV after suspected past exposure to HIV by e.g., bloodtransfusion, exchange of body fluids, bites, accidental needle stick, orexposure to patient blood during surgery. The term prevention includesprophylaxis of HIV infection and prophylaxis of the evolution of HIVinfection to AIDS.

For these purposes, the compositions comprising a combination of thepresent invention, whether co-formulated in a single formulation orformulated for simultaneous, separate or sequential use, may beadministered orally (including suspensions, capsules, tablets, sachets,solutions, suspensions, emulsions), parenterally (including subcutaneousinjections, intravenous, intramuscular, intrasternal injection orinfusion techniques), by inhalation spray (including nasal sprays), orrectally (including suppositories), in dosage unit formulationscontaining conventional non-toxic pharmaceutically acceptable carriers,adjuvants and vehicles.

Another aspect of the present invention concerns a kit or containercomprising a combination according to the invention combining an HIVprotease inhibitor of formula (1) and an inhibitor of cytochrome P₄₅₀,in an amount effective for use as a standard or reagent in a test orassay for determining the ability of potential pharmaceuticals toinhibit HIV protease, HIV growth, or both. This aspect of the inventionmay find its use in pharmaceutical research programs.

The combinations of the present invention can be used in high-throughputtarget-analyte assays such as those for measuring the efficacy of saidcombination in HIV treatment.

The combinations of the present invention can be used in phenotypicresistance monitoring assays, such as known recombinant assays, in theclinical management of resistance developing diseases such as HIV. Aparticularly useful resistance monitoring system is a recombinant virusassay known as the Antivirogram™. The Antivirogram™ is a highlyautomated, high throughput, second generation, recombinant assay thatcan measure susceptibility, especially viral susceptibility, to thecompositions of the present invention. (Hertogs K, de Bethune M P,Miller V et al. Antimicrob Agents Chemother, 1998; 42(2):269-276,incorporated by reference).

In accordance with the present invention there is further provided amethod for improving the pharmacokinetics of HIV protease inhibitor offormula (1) which is metabolized by cytochrome P₄₅₀ comprisingadministering to an individual in need of such treatment atherapeutically effective amount of a combination as described abovecomprising (a) said HIV protease inhibitor of formula (1) or anysubgroup thereof or a pharmaceutically acceptable salt thereof and (b)an inhibitor of cytochrome P450 or a pharmaceutically acceptable saltthereof.

The pharmacokinetics of an HIV protease inhibitor of formula (1) may bedescribed using pharmacokinetic parameters known to the person skilledin the art. Examples of such parameters include: t_(1/2) (half life),C_(min) (minimal concentration, trough concentration), C_(max) (maximalconcentration), AUC (area under the curve), time to maximalconcentration, steady state concentration (C_(ss)).

The present invention further relates to a method for treating HIVinfection and AIDS comprising administering to a patient in need of suchtreatment a combination of the present invention comprising atherapeutically effective amount of each component of said combination.

In the method of the present invention, the combination of HIV proteaseinhibitor of formula (1) or any subgroup thereof such as the compound offormula (4), and an inhibitor of P₄₅₀ cytochrome such as ritonavir, canbe administered concurrently in divided or single combination forms.

In another embodiment of the method of the invention, the administrationmay be performed with food (e.g., a high-fat meal) or without food. Theterm “with food” means the consumption of a meal either during or nomore than about one hour before or after administration of a one or bothcomponents of the combination according to the invention.

For an oral administration form, the compositions of the presentinvention can be mixed with suitable additives, such as excipients,stabilizers or inert diluents, and brought by means of the customarymethods into the suitable administration forms, such as tablets, coatedtablets, hard capsules, aqueous, alcoholic, or oily solutions. Examplesof suitable inert carriers are gum arabic, magnesia, magnesiumcarbonate, potassium phosphate, lactose, glucose, or starch, inparticular, corn starch. In this case, the preparation can be carriedout both as dry and as moist granules. Suitable oily excipients orsolvents are vegetable or animal oils, such as sunflower oil or codliver oil. Suitable solvents for aqueous or alcoholic solutions arewater, ethanol, sugar solutions, or mixtures thereof. Polyethyleneglycols and polypropylene glycols are also useful as further auxiliariesfor other administration forms. As immediate release tablets, thesecompositions may contain microcrystalline cellulose, dicalciumphosphate, starch, magnesium stearate and lactose and/or otherexcipients, binders, extenders, disintegrants, diluents and lubricantsknown in the art.

The oral administration of a combination comprising (a) an HIV proteaseinhibitor of formula (1) or any subgroup thereof such as the compound offormula (4) and (b) an inhibitor of P₄₅₀ cytochrome such as ritonavir,or a pharmaceutically acceptable salt or ester of either or both, issuitably accomplished by uniformly and intimately blending together asuitable amount of each component in the form of a powder, optionallyalso including a finely divided solid carrier, and encapsulating theblend in, for example, a hard gelatin capsule. The solid carrier caninclude one or more substances which act as binders, lubricants,disintegrating agents, coloring agents, and the like. Suitable solidcarriers include, for example, calcium phosphate, magnesium stearate,talc, sugars, lactose, dextrin, starch, gelatin, cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Oral administration of a composition comprising for example acombination of the compound of formula (4) and ritonavir in suitableproportions can also be accomplished by preparing capsules or tabletscontaining the desired amount of the compound of formula (4) only,optionally blended with a solid carrier as described above, and capsulescontaining the desired amount of ritonavir only. Compressed tabletscontaining the compound of formula (4) can be prepared by uniformly andintimately mixing the active ingredient with a solid carrier such asdescribed above to provide a mixture having the necessary compressionproperties, and then compacting the mixture in a suitable machine to theshape and size desired. Molded tablets maybe made by molding in asuitable machine, a mixture of powdered the compound of formula (4)moistened with an inert liquid diluent. Oral administration can also beaccomplished by preparing compressed or molded tablets containing thecompound of formula (4) as just described, the tablets of suitable sizefor insertion into standard capsules (e.g., hard gelatin capsules), andthen inserting the tablets into capsules containing a suitable amount ofritonavir powder.

When administered by nasal aerosol or inhalation, these compositions maybe prepared according to techniques well-known in the art ofpharmaceutical formulation and may be prepared as solutions in saline,employing benzyl alcohol or other suitable preservatives, absorptionpromoters to enhance bioavailability, fluorocarbons, and/or othersolubilizing or dispersing agents known in the art. Suitablepharmaceutical formulations for administration in the form of aerosolsor sprays are, for example, solutions, suspensions or emulsions of thecomponents of the compositions or their physiologically tolerable saltsin a pharmaceutically acceptable solvent, such as ethanol or water, or amixture of such solvents. If required, the formulation can alsoadditionally contain other pharmaceutical auxiliaries such assurfactants, emulsifiers and stabilizers as well as a propellant. Such apreparation customarily contains the active compounds in a concentrationfrom approximately 0.1 to 50%, in particular from approximately 0.3 to3% by weight.

For subcutaneous or intravenous administration, the active components ofthe compositions, if desired with the substances customary thereforesuch as solubilizers, emulsifiers or further auxiliaries, are broughtinto solution, suspension, or emulsion. The components of thecompositions can also be lyophilized and the lyophilizates obtainedused, for example, for the production of injection or infusionpreparations. Suitable solvents are, for example, water, physiologicalsaline solution or alcohols, e.g. ethanol, propanol, glycerol, inaddition also sugar solutions such as glucose or mannitol solutions, oralternatively mixtures of the various solvents mentioned. The injectablesolutions or suspensions may be formulated according to known art, usingsuitable non-toxic, parenterally-acceptable diluents or solvents, suchas mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodiumchloride solution, or suitable dispersing or wetting and suspendingagents, such as sterile, bland, fixed oils, including synthetic mono- ordiglycerides, and fatty acids, including oleic acid.

When rectally administered in the form of suppositories, theseformulations may be prepared by mixing the individual components of acomposition according to the invention with a suitable non-irritatingexcipient, such as cocoa butter, synthetic glyceride esters orpolyethylene glycols, which are solid at ordinary temperatures, butliquidify and/or dissolve in the rectal cavity to release the drug.

In order to enhance the solubility and/or the stability of thecomponents of a pharmaceutical composition according to the invention,it can be advantageous to employ α-, β- or γ-cyclodextrins or theirderivatives. In addition, co-solvents such as alcohols may improve thesolubility and/or the stability of the components of the pharmaceuticalcompositions. In the preparation of aqueous compositions, addition saltsof the components of said compositions are obviously more suitable dueto their increased water solubility.

Appropriate cyclodextrins are α, β- or γ-cyclodextrins (CDs) or ethersand mixed ethers thereof wherein one or more of the hydroxy groups ofthe anhydroglucose units of the cyclodextrin are substituted with alkyl,particularly methyl, ethyl or isopropyl, e.g. randomly methylated β-CD;hydroxyalkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl;carboxyalkyl, particularly carboxymethyl or carboxyethyl; alkylcarbonyl,particularly acetyl; alkyloxycarbonylalkyl or carboxyalkyloxyalkyl,particularly carboxymethoxypropyl or carboxyethoxypropyl;alkylcarbonyloxyalkyl, particularly 2-acetyloxypropyl. Especiallynoteworthy as complexants and/or solubilizers are β-CD, randomlymethylated β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD,2-hydroxyethyl-γ-CD, 2-hydroxypropyl-γ-CD and(2-carboxymethoxy)propyl-β-CD, and in particular 2-hydroxypropyl-β-CD(2-HP-β-CD). The term mixed ether denotes cyclodextrin derivativeswherein at least two cyclodextrin hydroxy groups are etherified withdifferent groups such as, for example, hydroxypropyl and hydroxyethyl.An interesting way of formulating the components of the compositions incombination with a cyclodextrin or a derivative thereof has beendescribed in EP-A-721,331. Although the formulations described thereinare with antifingal active ingredients, they are equally interesting forformulating the components of the compositions. Said formulations mayalso be rendered more palatable by adding pharmaceutically acceptablesweeteners and/or flavors.

More in particular, the combinations may be formulated in apharmaceutical formulation comprising a therapeutically effective amountof particles consisting of a solid dispersion comprising the followingcomponents: (a) an HIV protease inhibitor of formula (1) or any subgroupthereof, (b) an inhibitor of cytochrome P450 and (c) one or morepharmaceutically acceptable water-soluble polymers.

The term “a solid dispersion” defines a system in a solid state (asopposed to a liquid or gaseous state) comprising at least twocomponents, wherein one component is dispersed more or less evenlythroughout the other component or components. When said dispersion ofthe components is such that the system is chemically and physicallyuniform or homogenous throughout or consists of one phase as defined inthermodynamics, such a solid dispersion is referred to as “a solidsolution”. Solid solutions are preferred physical systems because thecomponents therein are usually readily bioavailable to the organisms towhich they are administered. The term “a solid dispersion” alsocomprises dispersions that are less homogenous throughout than solidsolutions. Such dispersions are not chemically and physically uniformthroughout or comprise more than one phase.

The water-soluble polymer in the particles is conveniently a polymerthat has an apparent viscosity of 1 to 100 mPa·s when dissolved in a 2%aqueous solution at 20° C. solution. Preferred water-soluble polymersare hydroxypropyl methylcelluloses or HPMC. HPMC having a methoxy degreeof substitution from about 0.8 to about 2.5 and a hydroxypropyl molarsubstitution from about 0.05 to about 3.0 are generally water soluble.Methoxy degree of substitution refers to the average number of methylether groups present per anhydroglucose unit of the cellulose molecule.Hydroxypropyl molar substitution refers to the average number of molesof propylene oxide which have reacted with each anhydroglucose unit ofthe cellulose molecule. The particles as defined hereinabove can beprepared by first preparing a solid dispersion of the components, andthen optionally grinding or milling that dispersion. Various techniquesexist for preparing solid dispersions including melt-extrusion,spray-drying and solution-evaporation, melt-extrusion being preferred.

It may further be convenient to formulate the components of thecombination in the form of nanoparticles which have a surface modifieradsorbed on the surface thereof in an amount sufficient to maintain aneffective average particle size of less than 1000 nm. Useful surfacemodifiers are believed to include those which physically adhere to thesurface of the antiretroviral agent but do not chemically bind to theantiretroviral agent. Suitable surface modifiers can preferably beselected from known organic and inorganic pharmaceutical excipients.Such excipients include various polymers, low molecular weightoligomers, natural products and surfactants. Preferred surface modifiersinclude nonionic and anionic surfactants.

Yet another interesting way of formulating the components of thecombination involves a pharmaceutical composition whereby the componentsare incorporated in hydrophilic polymers and applying this mixture as acoat film over many small beads, thus yielding a composition with goodbioavailability which can conveniently be manufactured and which issuitable for preparing pharmaceutical dosage forms for oraladministration. Said beads comprise (a) a central, rounded or sphericalcore, (b) a coating film of a hydrophilic polymer and an antiretroviralagent and (c) a seal-coating polymer layer. Materials suitable for useas cores in the beads are manifold, provided that said materials arepharmaceutically acceptable and have appropriate dimensions andfirmness. Examples of such materials are polymers, inorganic substances,organic substances, and saccharides and derivatives thereof.

The combinations of this invention can be administered to humans indosage ranges specific for each component comprised in saidcombinations. The components comprised in said combinations can beadministered together or separately. HIV protease inhibitor of formula(1) or any subgroup thereof, and the inhibitor of cytochrome P₄₅₀, or apharmaceutically acceptable salt or ester thereof, may have dosagelevels of the order of 0.02 to 5.0 grams-per-day.

When HIV protease inhibitor of formula (1) and the inhibitor of P₄₅₀cytochrome are administered in combination, the weight ratio of HIVprotease inhibitor of formula (1) to inhibitor of P₄₅₀ cytochrome issuitably in the range of from about 40:1 to about 1:15, or from about30:1 to about 1:15, or from about 15:1 to about 1:15, typically fromabout 10:1 to about 1:1, and more typically from about 8:1 to about 1:8.Also useful are weight ratios of HIV protease inhibitor of formula (1)to inhibitor of P₄₅₀ cytochrome ranging from about 6:1 to about 1:6, orfrom about 4:1 to about 1:4, or from about 3:1 to about 1:3, or fromabout 2:1 to about 1:2, or from about 1.5:1 to about 1:1.5. In oneaspect, the amount by weight of HIV protease inhibitor of formula (1) isequal to or greater than that of the inhibitor of P₄₅₀ cytochrome,wherein the weight ratio of HIV protease inhibitor of formula (1) toinhibitor of P₄₅₀ cytochrome is suitably in the range of from about 1:1to about 15:1, typically from about 1:1 to about 10:1, and moretypically from about 1:1 to about 8:1. Also useful are weight ratios ofHIV protease inhibitor of formula (1) to inhibitor of P₄₅₀ cytochromeranging from about 1:1 to about 6:1, or from about 1:1 to about 5:1, orfrom about 1:1 to about 4:1, or from about 3:2 to about 3:1, or fromabout 1:1 to about 2:1 or from about 1:1 to about 1.5:1.

According to one embodiment, the compound of formula (4) and ritonavirmay be co-administered twice a day, preferably orally, wherein theamount of the compound of formula (4) per dose is from about 10 to about2500 mg, and the amount of ritonavir per dose is from 10 to about 2500mg. In another embodiment, the amounts per dose for twice dailyco-administration are from about 50 to about 1500 mg of the compound offormula (4) and from about 50 to about 1500 mg of ritonavir. In stillanother embodiment, the amounts per dose for twice dailyco-administration are from about 100 to about 1000 mg of the compound offormula (4) and from about 100 to about 800 mg of ritonavir. In yetanother embodiment, the amounts per dose for twice dailyco-administration are from about 150 to about 800 mg of the compound offormula (4) and from about 100 to about 600 mg of ritonavir. In yetanother embodiment, the amounts per dose for twice dailyco-administration are from about 200 to about 600 mg of the compound offormula (4) and from about 100 to about 400 mg of ritonavir. In yetanother embodiment, the amounts per dose for twice dailyco-administration are from about 200 to about 600 mg of the compound offormula (4) and from about 20 to about 300 mg of ritonavir. In yetanother embodiment, the amounts per dose for twice dailyco-administration are from about 100 to about 400 mg of the compound offormula (4) and from about 40 to about 100 mg of ritonavir.

Exemplary combinations of the compound of formula (4) (mg)/ritonavir(mg) for twice daily dosage include 50/100, 100/100, 150/100, 200/100,250/100, 300/100, 350/100, 400/100, 450/100, 50/133, 100/133, 150/133,200/133, 250/133, 300/133, 50/150, 100/150, 150/150, 200/150, 250/150,50/200, 100/200, 150/200, 200/200, 250/200, 300/200, 50/300, 80/300,150/300, 200/300, 250/300, 300/300, 200/600, 400/600, 600/600, 800/600,1000/600, 200/666, 400/666, 600/666, 800/666, 1000/666, 1200/666,200/800, 400/800, 600/800, 800/800, 1000/800, 1200/800, 200/1200,400/1200, 600/1200, 800/1200, 1000/1200, and 1200/1200. Other exemplarycombinations of the compound of formula (4) (mg)/ritonavir (mg) fortwice daily dosage include 1200/400, 800/400, 600/400, 400/200, 600/200,600/100, 500/100, 400/50, 300/50, and 200/50.

According to another embodiment, the compound of formula (4) andritonavir may be co-adminstered once a day, preferably orally, whereinthe amount of the compound of formula (4) per dose is from about 10 toabout 2500 mg, and the amount of ritonavir per dose is from 10 to about2500 mg. In another embodiment, the amounts per dose for single dailyco-administration are from about 50 to about 1500 mg of the compound offormula (4) and from about 50 to about 1500 mg of ritonavir. In stillanother embodiment, the amounts per dose for single dailyco-administration are from about 100 to about 1000 mg of the compound offormula (4) and from about 100 to about 800 mg of ritonavir. In yetanother embodiment, the amounts per dose for single dailyco-administration are from about 150 to about 800 mg of the compound offormula (4) and from about 100 to about 600 mg of ritonavir. In yetanother embodiment, the amounts per dose for single dailyco-administration are from about 200 to about 600 mg of the compound offormula (4) and from about 100 to about 400 mg of ritonavir. In yetanother embodiment, the amounts per dose for single dailyco-administration are from about 200 to about 600 mg of the compound offormula (4) and from about 20 to about 200 mg of ritonavir. In yetanother embodiment, the amounts per dose for single dailyco-administration are from about 100 to about 400 mg of the compound offormula (4) and from about 40 to about 100 mg of ritonavir.

Exemplary combinations of the compound of formula (4) (mg)/ritonavir(mg) for single daily dosage include 50/100, 100/100, 150/100, 200/100,250/100, 300/100, 350/100, 400/100, 450/100, 50/133, 100/133, 150/133,200/133, 250/133, 300/133, 50/150, 100/150, 150/150, 200/150, 250/150,50/200, 100/200, 150/200, 200/200, 250/200, 300/200, 50/300, 80/300,150/300, 200/300, 250/300, 300/300, 200/600, 400/600, 600/600, 800/600,1000/600, 200/666, 400/666, 600/666, 800/666, 1000/666, 1200/666,200/800, 400/800, 600/800, 800/800, 1000/800, 1200/800, 200/1200,400/1200, 600/1200, 800/1200, 1000/1200, and 1200/1200. Other exemplarycombinations of the compound of formula (4) (mg)/ritonavir (mg) for oncedaily dosage include 1200/400, 800/400, 600/400, 400/200, 600/200,600/100, 500/100, 400/50, 300/50, 200/50.

It will be understood, however, that specific dose level and frequencyof dosage for any particular patient may be varied and will depend upona variety of factors including the activity of the specific compoundemployed, the metabolic stability and length of action of that compound,the age, body weight, general health, sex, diet, mode and time ofadministration, rate of excretion, drug combination, the severity of theparticular condition, and the host undergoing therapy.

The following examples are meant to be illustrative of the presentinvention. These examples are presented to exemplify the invention andare not to be construed as limiting the scope of the invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: Represents a mean concentration-time profile from a clinicaltrial with a combination of the compound of formula (4) with ritonavir,wherein the panel was subjected to oral administration of 200 mg thecompound of formula (4) o.d. (once daily) on day 1-14 and 100 mgritonavir o.d. on day 2-16. The bottom figure is on a logarithmic scale.

FIG. 2: Represents a mean concentration-time profile of the first 7 daysfrom a clinical trial with a combination of the compound of formula (4)with ritonavir, wherein the panel was subjected to oral administrationof 400 mg the compound of formula (4) o.d. on day 1-14 and 100 mgritonavir o.d. on day 2-16. The bottom figure is on a logarithmic scale.

FIG. 3: isobolograms for the combinations of the compound of formula (4)with HIV protease inhibitors. RTV: ritonavir; IDV: indinavir; NFV:nelfinavir; SQV: saquinavir; APV: amprenavir; TMC114: a compound offormula (4).

FIG. 4: Mean plasma concentration-time profiles of a single 800 mg ofthe compound of formula (4) dose in the absence and presence of‘steady-state’ concentrations of ritonavir (RTV) (600 mg b.i.d.) on asemi-logarithmic scale. (session 1, n=10 volunteers, the compound offormula (4) only; session 2, the compound of formula (4)+ritonavir, n=9volunteers: 6 volunteers had their dose of RTV lowered to 400 mg b.i.d.or discontinued RTV intake from day 4).

FIG. 5: Top: Mean plasma concentration-time profiles of the compound offormula (4) at different dose levels on a semi-logarithmic scale (on day1 and 7, n=6 per dose level, and on day 14, n=6 for 400 mg b.i.d., n=4for 800 mg b.i.d., n=3 for 800 mg t.i.d. and n=2 for 1200 mg t.i.d.).FIG. 5 bottom: Mean plasma concentration-time profiles of the compoundof formula (4) at different dose levels in the presence of low doses ofRTV on a semi-logarithmic scale (n=8 per panel). On day 1, a single doseof the compound of formula (4) was administered. From day 2 onwards,both the compound of formula (4) and RTV were administered. The regimensindicated in table consist of 200 mg of the compound of formula (4)/100mg ritonavir; 400 mg of the compound of formula (4)/100 mg ritonavir;300 mg of the compound of formula (4)/100 mg ritonavir; 600 mg of thecompound of formula (4)/200 mg ritonavir; 1200 mg of the compound offormula (4)/200 mg ritonavir.

FIG. 6: Adverse events that occurred in at least 2 individuals. Theresults are expressed as a percentage of the total group.

-   Placebo: the group to which a placebo was administered.-   Compound of formula (4): The adverse events that occurred in the    total population of individuals to whom the compound of formula (4)    was administered.-   Compound of formula (4)/RTV: The adverse events that occurred in the    total population of individuals to whom the compound of formula (4)    was administered in combination with ritonavir.

In order that those skilled in the art will better understand thepractice of the present invention, examples of the present invention aregiven below by way of illustration and not by way of limitation.

EXAMPLE 1 Influence of Ritonavir on the Pharmacokinetic Variables of aSelected Compound of Formula (1)

The pharmacokinetic variables for the compound of formula (4) wherecompared when the compound of formula (4) was administered alone to whenthe compound of formula (4) was co-administered to individuals to whichritonavir was given. The influence of ritonavir on the pharmacokineticsof a single dose of the compound of formula (4) is shown in FIG. 4.TABLE I Influence of ritonavir lowered to 400 mg b.i.d. or discontinuedRTV intake from day 4. Session I Session II Pharmacokinetics of thecompound (the compound of (the compound of of formula (4) formula (4)alone) formula (4) with (t_(max): median (range); mean ± SD) (n = 12)RTV) (n = 9) t_(max), h 0.8 (0.3-2.5) 1.0 (0.3-4.0) C_(max), ng/ml 3306± 1487 6220 ± 2826 AUC, ng · h/ml 10713 ± 3126  98729 ± 38481 t_(1/2), h11.3 ± 4.62 12.2 ± 4.03t_(max), h: time expressed in hours to obtain maximal concentration;Cmax, ng/ml: maximal concentration, expressed in ng/ml;AUC, ng · h/ml area under curve, expressed in ng × hours/ml;t_(1/2), h: half life, expressed in hours

EXAMPLE 2 Clinical Testing of a Combination of the Compound of Formula(4) with Ritonavir

This experiment investigated the influence of low doses of ritonavir onthe pharmacokinetics of the compound of formula (4) (n=8 per panel).

In panel A, 200 mg of the compound of formula (4) once daily (o.d.) wasgiven in combination with 100 mg ritonavir o.d. On day 1 a single 200 mgdose the compound of formula (4) was given without ritonavir. Theconcentration decreased to about 3 ng/ml after 24 h (FIG. 1). However,after combining 200 mg of the compound of formula (4) with 100 mgritonavir o.d., the C_(min) (minimum serum concentration) levels of thecompound of formula (4) increased to a mean of 560 ng/ml (range 90-1300ng/ml) (see table II). This means that addition of ritonavir caused a200-fold increase in C_(min) levels of the compound of formula (4).

As can be seen in the table below, C_(min) levels at day 14 werecomparable with the C_(min) levels at day 7. At day 14, mean C_(min)levels were 480 ng/ml, while C_(min) levels at day 7 were 562 ng/ml. Atboth days, the interindividual variation was high, as can be seen in thewide range of C_(min) levels. Both C_(max) (maximum serum concentration)and exposure levels were also comparable at both days.

In panel B, 400 mg the compound of formula (4) o.d. was given incombination with 100 mg ritonavir o.d. At this dose level, the meanC_(min) level at day 7 was 1226 ng/ml. This means that by increasing thecompound of formula (4) dose by 2, the C_(min) levels were alsoincreased by 2. Panel C has received 300 mg of the compound of formula(4) b.i.d. and 100 mg ritonavir b.i.d. for 14 days. Panel D has received600 mg of the compound of formula (4) o.d. and 200 mg ritonavir o.d. for14 days. Panel B has received 1200 mg of the compound of formula (4)o.d. and 200 mg ritonavir o.d. for 14 days. In comparison to panel D(600 mg of the compound of formula (4) o.d./200 mg ritonavir o.d.),C_(min) levels of panel E were not increased. At day 7, mean C_(min)levels were 1740 ng/ml for panel D and 1682 ng/ml for panel E. In bothpanels, C_(min) levels were decreased at day 14. At day 14, mean C_(min)levels were 1511 ng/ml for panel D and 1486 ng/ml for panel E.

In summary, co-administration of ritonavir led to much higher averageand trough plasma concentrations of the compound of formula (4) at lowertotal daily dose levels of the compound of formula (4). Peakconcentrations were lower or comparable. The safety profile of thecompound of formula (4) in combination with low doses of ritonavir wasgood (cfr. FIG. 6). Unexpectedly, the combination of the compound offormula (4) together with ritonavir resulted in a reduced incidence ofadverse effects. Unexpectedly, the combination has an improved safetyand tolerability profile compared to therapy with the compound offormula (4) alone.

No maculopapular rash was observed for the volunteers in panels A to D.This was unexpected because the average and C_(min) plasmaconcentrations of the compound of formula (4) were generally much higherthan those after the compound of formula (4) was administered alone (Ina study after 1200 mg of compound of formula (4) t.i.d. alone, therewere 4 out of 6 subjects, who developed maculopapular rash). C_(max)levels were lower or comparable.

In panel E, there was one volunteer with a clear maculopapular rash.Furthermore, there were two other volunteers with itching of the bodyand/or redness of the skin. It is likely that a certain compound (4)metabolite causes the maculopapular rash. Inhibition of CYP3A4metabolism will lead to lower levels of compound (4) metabolite and thusto a lower incidence of maculopapular rash. In panel E, there may beless inhibition due to the competition for the enzyme leading to morecompound (4) metabolite formation. The advantage of the combination ofRTV with the compound of formula (4) for therapy is furthersubstantiated by the pharmacokinetic data in tables III to IV.C_(ss, av) means the average steady state concentration. TABLE II Meanvalues and range of the C_(min), the C_(max), the C_(ss,av) and theAUC_(24 h) of the compound of formula (4) with low doses of RTV at thedifferent dose regimens (AUC = area under the curve i.e., total exposureof drug; C_(max) = maximum serum concentration, t.i.d. three times aday) Pharmacokinetics of the compound of formula (4) (mean (range))C_(min) (ng/ml) C_(max) (ng/ml) C_(ss,av) (ng/ml)* AUC_(24 h) (ng ·h/ml)** Panel A (200 mg compound of formula (4)/100 mg RTV o.d.) Day 7(n = 7)  562 (90-1290) 1750 (1190-3630)  857 (370-1739) 20562(8870-41725) Day 14 (n = 7)  480 (188-910) 1569 (1090-2370)  725(374-1192) 17409 (8971-28614) Panel B (400 mg compound of formula(4)/100 mg RTV o.d.) Day 7 (n = 8) 1226 (551-1850) 3540 (2440-5060) 1851(1157-2674) 44414 (27780-64178) Day 14 (n = 8)  981 (688-1710) 3125(2150-4650) 1703 (1108-3385) 40879 (26585-81238) Panel C (300 mgcompound of formula (4)/100 mg RTV b.i.d.) Day 7 (n = 8) 1539 (832-2500)2893 (2310-3780) 1892 (1095-2645) 45408 (26270-63486) Day 14 (n = 7)1650 (532-4350) 2854 (1910-5330) 1771 (970-4075) 42500 (23280-97800)Panel D (600 mg compound of formula (4)/200 mg RTV o.d.) Day 7 (n = 8)1740 (764-3290) 4196 (2890-5820) 2327 (1568-3036) 55839 (37621-72865)Day 14 (n = 8) 1511 (817-2720) 4628 (2790-5910) 2188 (1345-3914) 52505(32282-93925) Panel E (1200 mg compound of formula (4)/200 mg RTV o.d.)Day 7 (n = 8) 1682 (44-3090) 6438 (3680-9400) 2767 (908-4231) 66399(21799-101534) Day 14 (n = 7) 1486 (203-2980) 5453 (3520-7290) 2460(1122-3737) 59045 (26925-89679)*C_(ss, av) the dosing interval (in hours) corresponds to the AUC forthat dosing interval**Extrapolated AUC_(24 h) (for b.i.d. 2 * AUC_(12 h))

TABLE III Mean values and ranges of the C_(min), the C_(max), theC_(ss,av) and the AUC_(24 h) for the different dose regimens. (AUC =area under the curve i.e., total exposure of drug; C_(max) = maximumserum concentration, t.i.d. three times a day) Pharmacokinetics of thecompound of formula (4) (mean (range)) C_(min) (ng/ml) C_(max) (ng/ml)C_(ss,av) (ng/ml)* AUC_(24 h) (ng · h/ml)** Panel F (400 mg of thecompound of formula (4) b.i.d.) Day 7 (n = 6)  23 (5-45) 2458(1270-3540)  321 (203-458)  7702 (4864-10990) Day 14 (n = 6)  17 (6-30)2168 (1430-3270)  270 (185-333)  6477 (4438-7988) Panel G (800 mg of thecompound of formula (4) b.i.d.) Day 7 (n = 6)  64 (38-84) 5493(3800-6570) 1033 (606-1414) 24798 (14554-33938) Day 14 (n = 4)  44(32-52) 5755 (3950-7240)  951 (768-1103) 23202 (18442-26474) Panel H(800 mg of the compound of formula (4) t.i.d) Day 7 (n = 6) 197 (89-432)5227 (3910-6870) 1463 (849-1876) 35102 (20370-45024) Day 14 (n = 3) 161(57-303) 5143 (4880-5510) 1506 (1253-1933) 36131 (30075-46383) Panel I(1200 mg of the compound of formula (4) t.i.d) Day 7 (n = 6)   (125-504) 6332 (3130-8980) 1714 (966-2234) 41121 (23175-53616) Day 14 (n= 2) 142 (78-206) 8040 (7710-8370) 2027 (1909-2144) 48639 (45813-51465)C_(ss, av) time dosing interval corresponds to the AUC for that dosinginterval**Extrapolated AUC_(24 h) (for b.i.d. 2 * AUC_(12 h), for t.i.d. 3 *AUC_(8 h))

TABLE IV Mean values and range of C_(min), C_(max), C_(ss,av) andAUC_(24 h) for the compound of formula (4) at different dosages with lowdoses of RTV Pharmacokinetics of the compound of formula (4) (mean(range)) C_(min) (ng/ml) C_(max) (ng/ml) C_(ss,av) (ng/ml)* AUC_(24 h)(ng · h/ml)** Panel J (300 mg compound of formula (4)/100 mg RTV b.i.d.)Day 14 (n = 12) 1175 (684-1890) 4440 (2490-10200) 2129 (1145-3384) 51092(27476-81226) Panel K (600 mg compound of formula (4)/100 mg RTV b.i.d.)Day 14 (n = 12) 1819 (612-5270) 5738 (2760-9160) 2915 (1049-6404) 69953(25174-153696) Panel L (900 mg compound of formula (4)/100 mg RTV o.d.)Day 14 (n = 9) 1438 (468-2140) 6549 (4710-7870) 2651 (1833-3018) 63611(43985-72430)*C_(ss, av) the dosing interval (in hours) corresponds to the AUC forthat dosing interval**Extrapolated AUC_(24 h) (for b.i.d. 2 * AUC_(12 h))

EXAMPLE 3 Synergy of Combinations of the Compound of Formula (4) andOther HIV Protease Inhibitors

The activity of combinations of the compound of formula (4) with thecurrent anti-HIV drugs at three different molar ratios was determined inHIV-1/LAI infected MT4 cells. The results were analyzed according to theisobologram method described by Chou and Talalay (1984).

The results are presented as the mean of three separate experiments. Thecombination index (CI) for each combination was determined. A CI valuebetween 0.8 and 1.2 reflects additive inhibition of the combinedcompounds, a value below 0.8 indicates a synergy between the twomolecules, whereas a value greater than 1.2 is indicative of antagonism.

The compound of formula (4) exhibited no antagonism with any of thetested drugs. It showed additive inhibition with indinavir (CI:0.87-0.92), lopinavir (CI: 0.85-0.95) and saquinavir (0.94-1.0), at allmolar ratios, and it showed synergy with amprenavir (CI: 0.65-0.77),nelfinavir (0.61-0.80) and ritonavir (0.66-0.81), at all molar ratios.

These results are also illustrated in FIG. 3 where the isobolograms forthe combinations of the compound of formula (4) with HIV proteaseinhibitors respectively are plotted. Whereas a straight line representsadditive inhibition by two inhibitors, a curve towards the origin of theaxes indicates synergy. The latter is observed for combinations withamprenavir, nelfinavir and ritonavir.

EXAMPLE 4 Non-Limiting Examples of HIV Protease Inhibitor of Formula (1)

TABLE A

R⁴ R¹

—CH₃

—CH₃

—(CH₂)₂—NH- —CH₃ (2-pyridinyl) —(CH₂)₂—NH- (2-pyridinyl)

—(CH₂)₂—NH- (2-pyridinyl)

—(CH₂)₂—NH- (2-pyridinyl)

—(CH₂)₂—NH- (2-pyridinyl)

—(CH₂)₂—NH- (2-pyridinyl)

—(CH₂)₂—NH- (2-pyridinyl)

—(CH₂)₂—NH- (2-pyridinyl)

—(CH₂)₂—NH- (2-pyridinyl)

—(CH₂)₂—NH- (2-pyridinyl)

—(CH₂)₂—NH- (2-pyridinyl)

—(CH₂)₂—NH- (2-pyridinyl)

—(CH₂)₂—NH- (2-pyridinyl)

—(CH₂)₂—NH- (2-pyridinyl)

—(CH₂)₂—NH- (2-pyridinyl)

—(CH₂)₂—NH- (2-pyridinyl)

—(CH₂)₂—NH- (2-pyridinyl)

—(CH₂)₂—NH- (2-pyridinyl)

—(CH₂)₂—NH- (2-pyridinyl)

—(CH₂)₂—NH- (2-pyridinyl)

—(CH₂)₂—NH- (2-pyridinyl)

—(CH₂)₂—NH- (2-pyridinyl)

—(CH₂)₂—NH- (2-pyridinyl)

—(CH₂)₂—NH- (2-pyridinyl)

—CH₃

—CH₃

—CH₃

TABLE B

R_(a) —NH—CO—CH₃ —NH—COO—C₂H₅ —NH—CO—CH₂—N(CH₃)₂ —NH—(CH₂)₂—N(CH₃)₂

—NH—CH₂—COOCH₃

—N(CH₃)—COCH₃

—NH—CO—CH₂—N(CH₃)₂

—NH—(CH₂)₂—N(CH₃)₂

—NH—(CH₂)₃—N(CH₃)₂ —NH—(CH₂)₂—NH(CH₃)

TABLE C

R_(a) R_(b) —(CH₂)₂—NH-(2-pyridinyl) —NH—CO—CH₃

TABLE D

R_(a) —NH—CO—CH₃ —NH—COO—C₂H₅ —NH—CO—CH₂—N(CH₃)₂ —NH—(CH₂)₂—N(CH₃)₂

—NH—CH₂—COOCH₃

—N(CH₃)—COCH₃

—NH—CO—CH₂—N(CH₃)₂

—NH—(CH₂)₂—N(CH₃)₂

—NH(CH₂)₃—N(CH₃)₂ —NH—(CH₂)₂—NMH(CH₃)

—NH—(CH₂)₂—OH

—NH—CH₃

TABLE E

R_(a) R_(b) —(CH₂)₂—NH-(2- —NH—CO—CH₃ pyridinyl)

Obviously, numerous modifications and variations of the presentinvention are possible in the light of the above teachings. It istherefore to be understood that within the scope of the appended claims,the invention may be practiced otherwise than as specifically describedherein.

1. Combination comprising (a) an HIV protease inhibitor of formula (1)or a pharmaceutically acceptable salt or ester thereof and (b) aninhibitor of cytochrome P₄₅₀, wherein the HIV protease inhibitor offormula (1) has the formula

wherein, L is —C(═O)—, —O—C(═O)—, —NR¹⁰—C(═O)—, —O-alkanediyl-C(═O)—,—NR¹⁰-alkanediyl-C(═O)—, —C═S, —S(═O)₂—, —O—S(═O)₂—, —NR¹⁰—S(═O)₂,whereby either the C(═O) group or the S(═O)₂ group is attached to theNR¹⁰ moiety; wherein R¹⁰ is hydrogen, alkyl, alkenyl, aralkyl,cycloalkyl, cycloalkylalkyl, aryl, Het¹, Het¹alkyl, Het² or Het²alkyl;R¹ is hydrogen, alkyl, alkenyl, alkynyl, alkanediyl, alkylcarbonyl,alkyloxy, alkyloxyalkyl, alkyloxycarbonyl, alkanoyl, cycloalkyl,cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkanoyl,cycloalkylalkoxycarbonyl, aryl, aralkyl, arylalkenyl, arylcarbonyl,aryloxycarbonyl, aralkoxycarbonyl, aryloxyalkyl, haloalkyl,hydroxyalkyl, aralkanoyl, aroyl, aryloxycarbonylalkyl, aryloxyalkanoyl,Het¹, Het¹alkyl, Het¹oxy, Het¹oxyalkyl, Het¹aryl, Het¹aralkyl,Het¹cycloalkyl, Het¹carbonyl, Het¹alkoxycarbonyl, Het¹oxycarbonyl,Het¹alkanoyl, Het¹aralkanoyl, Het¹aryloxyalkyl, Het¹aryloxycarbonyl,Het¹aralkoxycarbonyl, Het¹aroyl, Het², Het²oxy, Het²alkyl; Het²oxyalkyl,Het²aralkyl, Het²cycloalkyl, Het²aryl, Het²carbonyl, Het²oxycarbonyl,Het²alkanoyl, Het²alkoxycarbonyl, Het²aralkanoyl, Het²aralkoxycarbonyl,Het²aryloxycarbonyl, Het²aroyl, Het²aryloxyalkyl, aminocarbonyl,aminoalkanoyl, aminoalkyl, optionally substituted by one or moresubstituents independently selected from the group comprising alkyl,aralkyl, aryl, Het¹, Het², cycloalkyl, alkyloxycarbonyl, carboxyl,aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl,alkylS(═O)_(t), hydroxy, cyano, halogen or amino optionally mono- ordisubstituted wherein the substituents are independently selected fromthe group comprising alkyl, aryl, aralkyl, aryloxy, arylamino, arylthio,aryloxyalkyl, arylaminoalkyl, aralkoxy, alkylthio, alkoxy,aryloxyalkoxy, arylaminoalkoxy, aralkylamino, aryloxyalkylamino,arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino, aralkylthio,aryloxyalkylthio, arylaminoalkylthio, arylthioalkylthio, alkylamino,cycloalkyl, cycloalkylalkyl, Het¹, Het², Het¹alkyl, Het²alkyl,Het¹amino, Het²amino, Het¹alkylamino, Het²alkylamino, Het¹thio,Het²thio, Het¹alkylthio, Het²alkylthio, Het¹oxy and Het²oxy, OR⁷, SR⁷,SO₂NR⁷R⁸, SO₂N(OH)R⁷, CN, CR⁷═NR⁸, S(O)R⁷, SO₂R⁷, CR⁷═N(OR⁸), N₃, NO₂,NR⁷R⁸, N(OH)R⁷, C(O)R⁷, C(S)R⁷, CO₂R⁷, C(O)SR⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸,C(O)N(OH)R⁸, C(S)N(OH)R⁷, NR⁷C(O)R⁸, NR⁷C(S)R⁸, N(OH)C(O)R⁷,N(OH)C(S)R⁷, NR⁷CO₂R⁸, NR⁷C(O)NR⁸R⁹, and NR⁷C(S)NR⁸R⁹, N(OH)CO₂R⁷,NR⁷C(O)SR⁸, N(OH)C(O)NR⁷R⁸, N(OH)C(S)NR⁷R⁸, NR⁷C(O)N(OH)R⁸,NR⁷C(S)N(OH)R⁸, NR⁷SO₂R⁸, NHSO₂NR⁷R⁸, NR⁷SO₂NHR⁸, P(O)(OR⁷)(OR⁸),wherein t is an integer selected from 1 or 2, R⁷, R⁸ and R⁹ are eachindependently selected from the group comprising H, alkyl, alkenyl, andalkynyl; R² is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl,alkyloxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl,cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl,aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, aryloxyalkanoyl,Het¹carbonyl, Het²carbonyl, Het¹oxycarbonyl, Het²oxycarbonyl,Het¹alkanoyl, Het²alkanoyl, Het¹, Het²alkoxycarbonyl, Het¹aralkanoyl,Het²aralkanoyl, Het¹aralkoxycarbonyl, Het²aralkoxycarbonyl,Het¹aryloxycarbonyl, Het²aryloxycarbonyl, Het¹aroyl, Het²aroyl,cycloalkyl, aryloxyalkyl, Het¹aryloxyalkyl, Het²aryloxyalkyl,hydroxyalkyl, aminocarbonyl, aminoalkanoyl, and mono- and disubstitutedaminocarbonyl and mono- and disubstituted aminoalkanoyl radicals whereinthe substituents are independently selected from the group comprisingalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl,heteroaralkyl, heterocycloalkyl, hetero cycloalkylalkyl radicals, orwherein said aminoalkanoyl radical is disubstituted, said substituentsalong with the nitrogen atom to which they are attached form a Het¹,Het², Het¹or Het²aryl radical; R³ is alkyl, aryl, cycloalkyl,cycloalkylalkyl, Het¹, Het², Het¹aryl, Het²aryl, or aralkyl optionallysubstituted with one or more substituent independently selected from thegroup comprising alkyl, halo, nitro, cyano, CF₃, —OR⁵, and —SR⁵,(CH₂)_(p)R⁶, OR⁷, SR⁷, CN, N₃, C(O)R⁷, C(S)R⁷, CO₂R⁷, C(O)SR⁷, NR⁷R⁸,NR⁷C(O)R⁸, NR⁷C(S)R⁸, NR⁷CO₂R⁸, C(O)NR⁷R⁸, C(S)NR⁷R⁸, and NR⁷C(O)SR⁸,wherein R⁵ is a radical selected from the group comprising hydrogen andalkyl, wherein: p is an integer from 0 to 5; R⁶ is cycloalkyl, Het¹,aryl, or Het² in which at least one hydrogen atom is optionallysubstituted with one or more substituents independently selected fromthe group comprising a halogen, OH, OCH₃, NH₂, NO₂, SH, and CN, whereinR⁷ and R⁸ have the same meaning as that defined above; R⁴ is hydrogen,alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(alkyl)aminocarbonyl, cycloalkyl, cycloalkylalkyl, Het¹, Het²,Het¹alkyl, Het²alkyl, Het¹cycloalkyl, Het²cycloalkyl, Het¹aryl,Het²aryl, alkylthioalkyl, alkenyl, alkynyl, alkyloxyalkyl, haloalkyl,alkylsulfonylalkyl, hydroxyalkyl, aralkyl, aminoalkyl, or alkyl,optionally substituted with one or more substituents independentlyselected from comprising aryl, Het¹, Het², cycloalkyl, alkyloxycarbonyl,carboxyl, aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl,alkylS(═O)_(t), hydroxy, cyano, nitro, thio, halogen or amino optionallymono- or disubstituted wherein the substituents are independentlyselected from the group comprising alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, Het¹, Het², Het¹alkyl and Het²alkyl.
 2. Combinationaccording to claim 1, comprising (a) a HIV protease inhibitor of formula(2) or a pharmaceutically acceptable salt or ester thereof and (b) aninhibitor of cytochrome P₄₅₀ or a pharmaceutically acceptable salt orester thereof,

wherein, R¹ is hydrogen, alkyl, alkenyl, alkynyl, alkanediyl,alkylcarbonyl, alkyloxy, alkyloxyalkyl, alkyloxycarbonyl, alkanoyl,cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkanoyl,cycloalkylalkoxycarbonyl, aryl, aralkyl, arylalkenyl, arylcarbonyl,aryloxycarbonyl, aralkoxycarbonyl, aryloxyalkyl, haloalkyl,hydroxyalkyl, aralkanoyl, aroyl, aryloxycarbonylalkyl, aryloxyalkanoyl,Het¹, Het¹alkyl, Het¹oxy, Het¹oxyalkyl, Het¹aryl, Het¹aralkyl,Het¹cycloalkyl, Het¹carbonyl, Het¹alkoxycarbonyl, Het¹oxycarbonyl,Het¹alkanoyl, Het¹ aralkanoyl, Het¹aryloxyalkyl, Het¹aryloxycarbonyl,Het¹aralkoxycarbonyl, Het¹aroyl, Het², Het²oxy, Het²alkyl; Het²oxyalkyl,Het²aralkyl, Het²cycloalkyl, Het²aryl, Het²carbonyl, Het²oxycarbonyl,Het²alkanoyl, Het²alkoxycarbonyl, Het²aralkanoyl, Het²aralkoxycarbonyl,Het²aryloxycarbonyl, Het²aroyl, Het²aryloxyalkyl, aminocarbonyl,aminoalkanoyl, aminoalkyl, optionally substituted by one or moresubstituents independently selected from the group comprising alkyl,aralkyl, aryl, Het¹, Het², cycloalkyl, alkyloxycarbonyl, carboxyl,aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl,alkylS(═O)_(t), hydroxy, cyano, halogen or amino optionally mono- ordisubstituted wherein the substituents are independently selected fromthe group comprising alkyl, aryl, aralkyl, aryloxy, arylamino, arylthio,aryloxyalkyl, arylaminoalkyl, aralkoxy, alkylthio, alkoxy,aryloxyalkoxy, arylaminoalkoxy, aralkylamino, aryloxyalkylamino,arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino, aralkylthio,aryloxyalkylthio, arylaminoalkylthio, arylthioalkylthio, alkylamino,cycloalkyl, cycloalkylalkyl, Het¹, Het², Het¹alkyl, Het²alkyl,Het¹amino, Het²amino, Het¹alkylamino, Het²alkylamino, Het¹thio,Het²thio, Het¹alkylthio, Het²alkylthio, Het¹oxy and Het²oxy, wherein tis an integer between 1 and 2; R² is hydrogen or alkyl; R3 is alkyl,aryl, cycloalkyl, cycloalkylalkyl, or aralkyl radical; R4 is hydrogen,alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(alkyl)aminocarbonyl, cycloalkyl, alkenyl, alkynyl, or alkyl,optionally substituted with one or more substituents independentlyselected from the group comprising aryl, Het¹, Het², cycloalkyl,alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(alkyl)aminocarbonyl, aminosulfonyl, alkylS(═O)_(t), hydroxy, cyano,halogen or amino optionally mono- or disubstituted wherein thesubstituents are independently selected from the group comprising alkyl,aryl, aralkyl, cycloalkyl, cycloalkylalkyl, Het¹, Het², Het¹alkyl andHet²alkyl.
 3. Combination according to claim 1, comprising (a) an HIVprotease inhibitor of formula (3) or a pharmaceutically acceptable saltor ester thereof and (b) an inhibitor of cytochrome P₄₅₀,

wherein, R¹ is cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl,cycloalkylalkanoyl, cycloalkylalkoxycarbonyl, aryl, aralkyl,arylalkenyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl,aryloxyalkyl, haloalkyl, hydroxyalkyl, aralkanoyl, aroyl,aryloxycarbonylalkyl, aryloxyalkanoyl, Het¹, Het¹alkyl, Het¹oxy, Het¹,Het¹aryl, Het¹aralkyl, Het¹cycloalkyl, Het¹carbonyl, Het¹alkoxycarbonyl,Het¹oxycarbonyl, Het¹alkanoyl, Het¹aralkanoyl, Het¹aryloxyalkyl, Het¹,Het¹, Het¹aroyl, Het², Het²oxy, Het²alkyl; Het²oxyalkyl, Het²aralkyl,Het²cycloalkyl, Het²aryl, Het²carbonyl, Het²oxycarbonyl, Het²alkanoyl,Het²alkoxycarbonyl, Het²aralkanoyl, Het²aralkoxycarbonyl,Het²aryloxycarbonyl, Het²aroyl, Het²aryloxyalkyl, optionally substitutedby one or more substituents independently selected from the groupcomprising alkyl, aralkyl, aryl, Het¹, Het², cycloalkyl,alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(alkyl)aminocarbonyl, aminosulfonyl, alkylS(═O)_(t), hydroxy, cyano,halogen or amino optionally mono- or disubstituted wherein thesubstituents are independently selected from the group comprising alkyl,aryl, aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl,arylaminoalkyl, aralkoxy, alkylthio, alkoxy, aryloxyalkoxy,arylaminoalkoxy, aralkylamino, aryloxyalkylamino, arylaminoalkylamino,arylthioalkoxy, arylthioalkylamino, aralkylthio, aryloxyalkylthio,arylaminoalkylthio, arylthioalkylthio, alkylamino, cycloalkyl,cycloalkylalkyl, Het¹, Het², Het¹alkyl, Het²alkyl, Het¹amino, Het²amino,Het¹alkylamino, Het²alkylamino, Het¹thio, Het²thio, Het¹, Het²alkylthio,Het¹and Het²oxy, wherein t is an integer between 1 and 2, and R⁴ isalkyl, optionally substituted with one or more substituent independentlyselected from the group comprising aryl, Het¹, Het², cycloalkyl, andamino optionally mono- or disubstituted wherein the substituents areindependently selected from the group comprising alkyl, aryl, Het¹,Het².
 4. Combination according to claim 1, comprising (a) an HIVprotease inhibitor as depicted in Table A or Table B or Table C or TableD or Table E or a pharmaceutically acceptable salt or ester thereof and(b) an inhibitor of cytochrome P₄₅₀.
 5. Combination according to claim1, comprising (a) an HIV protease inhibitor of formula (4) or apharmaceutically acceptable salt or ester thereof and (b) an inhibitorof cytochrome P₄₅₀ wherein the compound of formula (4) has the formula


6. Combination according to claim 1, wherein said inhibitor ofcytochrome P₄₅₀ is selected from ritonavir, ketoconazole, cimetidine andbergamottin.
 7. A combination according to claim 1, characterized by acombination index of about 0.8 or lower.
 8. Combination according toclaim 1, comprising (a) an HIV protease inhibitor of formula (4) or apharmaceutically acceptable salt or ester thereof and (b) ritonavir or apharmaceutically acceptable salt or ester thereof.
 9. Pharmaceuticalcomposition comprising a therapeutic amount of a combination accordingto claim 1 and a pharmaceutically acceptable excipient.
 10. Productcontaining (a) a pharmaceutical composition comprising a therapeuticamount of an HIV protease inhibitor of formula (1), and (b) apharmaceutical composition comprising a therapeutic amount of aninhibitor of cytochrome P₄₅₀, as a combined preparation forsimultaneous, separate or sequential use in HIV therapy.
 11. Acombination according to claim 1 for use as a medicament.
 12. A methodof manufacturing a medicament for treating, preventing or combatinginfection or disease associated with retrovirus infection in a mammalcomprising mixing a combination according to claim 1 and apharmaceutically acceptable excipient.
 13. (canceled)
 14. (canceled) 15.(canceled)
 16. (canceled)
 17. (canceled)
 18. A method of improving thepharmacokinetics of a compound of formula (I) relative to thepharmacokinetics of said compound of formula (I) administered alone,comprising forming a combination as in claim
 1. 19. (canceled)
 20. Amethod according to claim 18, wherein the amount of the cytochrome P₄₅₀inhibitor is sufficient for increasing at least one of thepharmacokinetic variables selected from C_(min), C_(max), AUC at 12hours, relative to the pharmacokinetic variables when a compound offormula (I) is administered alone.
 21. A method according to claim 18,wherein the amount of the cytochrome P450 inhibitor is sufficient forincreasing at least one of the pharmacokinetic variables of a compoundof formula (I) selected from C_(min), C_(max), C_(ss,av), AUC at 12hours, or AUC at 24 hours, relative to said at least one pharmacokineticvariable when a compound of formula (I) is administered alone.
 22. Amethod for improving the pharmacokinetics of an HIV protease inhibitorof formula (I) comprising administering to an individual in need of suchtreatment a therapeutically effective amount of a combination accordingto claim
 1. 23. A method for treating HIV infection and AIDS comprisingadministering to a patient in need of such treatment a combinationaccording to claim 1, comprising a therapeutically effective amount ofeach component of said combination.